rs114258385

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.5617G>A(p.Val1873Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,612,944 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V1873V) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0071 ( 17 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 9 hom. )

Consequence

ABCA12
NM_173076.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0940

Publications

3 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:

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=0.0039067864).

BP6

Variant 2-214970346-C-T is Benign according to our data. Variant chr2-214970346-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00706 (1074/152098) while in subpopulation AFR AF = 0.0249 (1035/41514). AF 95% confidence interval is 0.0237. There are 17 homozygotes in GnomAd4. There are 508 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA12	NM_173076.3 link	c.5617G>A	p.Val1873Ile	missense_variant	Exon 37 of 53	ENST00000272895.12	NP_775099.2	Q86UK0-1B3KVV3
ABCA12	NM_015657.4 link	c.4663G>A	p.Val1555Ile	missense_variant	Exon 29 of 45		NP_056472.2	Q86UK0-2B3KVV3
ABCA12	XM_011510951.3 link	c.5626G>A	p.Val1876Ile	missense_variant	Exon 37 of 53		XP_011509253.1
ABCA12	NR_103740.2 link	n.6115G>A		non_coding_transcript_exon_variant	Exon 39 of 55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA12	ENST00000272895.12 link	c.5617G>A	p.Val1873Ile	missense_variant	Exon 37 of 53	1	NM_173076.3	ENSP00000272895.7		Q86UK0-1
ABCA12	ENST00000389661.4 link	c.4663G>A	p.Val1555Ile	missense_variant	Exon 29 of 45	1		ENSP00000374312.4		Q86UK0-2

Frequencies

GnomAD3 genomes

AF:

0.00703

AC:

1068

AN:

151980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0249

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00138

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000883

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00189

AC:

473

AN:

250838

AF XY:

0.00134

show subpopulations

Gnomad AFR exome

AF:

0.0252

Gnomad AMR exome

AF:

0.00119

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000741

AC:

1083

AN:

1460846

Hom.:

Cov.:

AF XY:

0.000665

AC XY:

483

AN XY:

726746

show subpopulations

African (AFR)

AF:

0.0256

AC:

857

AN:

33426

American (AMR)

AF:

0.00134

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39610

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00295

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

1111324

Other (OTH)

AF:

0.00156

AC:

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

100

150

200

250

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00706

AC:

1074

AN:

152098

Hom.:

Cov.:

AF XY:

0.00683

AC XY:

508

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.0249

AC:

1035

AN:

41514

American (AMR)

AF:

0.00138

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000883

AC:

AN:

67934

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

109

164

218

273

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:

0.00289

Hom.:

Bravo

AF:

0.00833

ESP6500AA

AF:

0.0241

AC:

106

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00228

AC:

277

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 04, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital ichthyosis of skin

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

CADD

Benign

5.9

(source)

DANN

Benign

0.51

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.67

T;T

MetaRNN

Benign

0.0039

T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

0.51

N;.

PhyloP100

0.094

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.20

N;N

REVEL

Benign

0.28

Sift

Benign

0.68

T;T

Sift4G

Benign

0.52

T;T

Polyphen

0.0010

B;B

Vest4

0.054

MVP

0.55

MPC

0.15

ClinPred

0.0021

GERP RS

1.4

Varity_R

0.023

gMVP

0.27

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

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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