rs148979792

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_173076.3(ABCA12):c.1765C>A(p.Pro589Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00905 in 1,614,056 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P589R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0069 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0093 ( 84 hom. )

Consequence

ABCA12
NM_173076.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 4.56

Publications

12 publications found

Variant links:

Genes affected

ABCA12 (HGNC:14637): (ATP binding cassette subfamily A member 12) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, and White). This encoded protein is a member of the ABC1 subfamily, which is the only major ABC subfamily found exclusively in multicellular eukaryotes. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ABCA12 Gene-Disease associations (from GenCC):

autosomal recessive congenital ichthyosis 4B
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, PanelApp Australia, Orphanet, G2P
autosomal recessive congenital ichthyosis 4A
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
congenital non-bullous ichthyosiform erythroderma
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
lamellar ichthyosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ABCA12 links:

ENSG00000227769 (HGNC:):

ENSG00000227769 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006954968).

BP6

Variant 2-215018025-G-T is Benign according to our data. Variant chr2-215018025-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00692 (1054/152260) while in subpopulation AMR AF = 0.0127 (194/15294). AF 95% confidence interval is 0.0112. There are 6 homozygotes in GnomAd4. There are 486 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ABCA12	NM_173076.3 link	c.1765C>A	p.Pro589Thr	missense_variant	Exon 14 of 53	ENST00000272895.12	NP_775099.2
ABCA12	NM_015657.4 link	c.811C>A	p.Pro271Thr	missense_variant	Exon 6 of 45		NP_056472.2
ABCA12	XM_011510951.3 link	c.1765C>A	p.Pro589Thr	missense_variant	Exon 14 of 53		XP_011509253.1
ABCA12	NR_103740.2 link	n.2207C>A		non_coding_transcript_exon_variant	Exon 15 of 55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ABCA12	ENST00000272895.12 link	c.1765C>A	p.Pro589Thr	missense_variant	Exon 14 of 53	1	NM_173076.3	ENSP00000272895.7
ABCA12	ENST00000389661.4 link	c.811C>A	p.Pro271Thr	missense_variant	Exon 6 of 45	1		ENSP00000374312.4
ENSG00000227769	ENST00000617699.1 link	n.278+276G>T		intron_variant	Intron 3 of 3	5
ENSG00000227769	ENST00000627811.1 link	n.73+4808G>T		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.00693

AC:

1055

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00215

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0127

Gnomad ASJ

AF:

0.00433

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0105

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.00705

AC:

1773

AN:

251376

AF XY:

0.00694

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.0112

Gnomad ASJ exome

AF:

0.00317

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00185

Gnomad NFE exome

AF:

0.0106

Gnomad OTH exome

AF:

0.00962

GnomAD4 exome

AF:

0.00927

AC:

13547

AN:

1461796

Hom.:

Cov.:

AF XY:

0.00895

AC XY:

6507

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

33480

American (AMR)

AF:

0.0116

AC:

521

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00325

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39684

South Asian (SAS)

AF:

0.000499

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00191

AC:

102

AN:

53380

Middle Eastern (MID)

AF:

0.00520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0110

AC:

12198

AN:

1111980

Other (OTH)

AF:

0.00848

AC:

512

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

699

1398

2096

2795

3494

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

460

920

1380

1840

2300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00692

AC:

1054

AN:

152260

Hom.:

Cov.:

AF XY:

0.00653

AC XY:

486

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.00214

AC:

AN:

41556

American (AMR)

AF:

0.0127

AC:

194

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00433

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000622

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0105

AC:

711

AN:

68020

Other (OTH)

AF:

0.0132

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

111

166

222

277

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00901

Hom.:

Bravo

AF:

0.00762

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0101

AC:

ExAC

AF:

0.00683

AC:

829

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0120

EpiControl

AF:

0.0115

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ABCA12: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital ichthyosis of skin

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Autosomal recessive congenital ichthyosis 4B;C1832550:Autosomal recessive congenital ichthyosis 4A

Benign:1

Mar 23, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

T;.

Eigen

Benign

-0.064

Eigen_PC

Benign

-0.045

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.78

T;T

MetaRNN

Benign

0.0070

T;T

MetaSVM

Benign

-0.30

MutationAssessor

Benign

2.0

M;.

PhyloP100

4.6

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.2

N;N

REVEL

Uncertain

0.31

Sift

Uncertain

0.025

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.84

P;B

Vest4

0.60

MVP

0.78

MPC

0.24

ClinPred

0.036

GERP RS

5.0

Varity_R

0.13

gMVP

0.52

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over