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.1892G>A(p.Arg631Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,614,026 control chromosomes in the GnomAD database, including 45 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R631W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0027 ( 3 hom., cov: 31)

Exomes 𝑓: 0.0017 ( 42 hom. )

Consequence

ABCA12
NM_173076.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.519

Publications

6 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=0.0032784045).

BP6

Variant 2-215015554-C-T is Benign according to our data. Variant chr2-215015554-C-T is described in ClinVar as Benign. ClinVar VariationId is 262822.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 = 0.00274 (417/152224) while in subpopulation AMR AF = 0.0153 (234/15294). AF 95% confidence interval is 0.0137. There are 3 homozygotes in GnomAd4. There are 235 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173076.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ABCA12	NM_173076.3	MANE Select	c.1892G>A	p.Arg631Gln	missense	Exon 15 of 53	NP_775099.2
ABCA12	NM_015657.4		c.938G>A	p.Arg313Gln	missense	Exon 7 of 45	NP_056472.2
ABCA12	NR_103740.2		n.2334G>A		non_coding_transcript_exon	Exon 16 of 55

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ABCA12	ENST00000272895.12	TSL:1 MANE Select	c.1892G>A	p.Arg631Gln	missense	Exon 15 of 53	ENSP00000272895.7
ABCA12	ENST00000389661.4	TSL:1	c.938G>A	p.Arg313Gln	missense	Exon 7 of 45	ENSP00000374312.4
ENSG00000227769	ENST00000617699.1	TSL:5	n.191-2108C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00272

AC:

413

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0151

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0120

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00774

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00669

AC:

1682

AN:

251296

AF XY:

0.00540

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.0383

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0116

Gnomad FIN exome

AF:

0.00448

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00174

AC:

2540

AN:

1461802

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

1169

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33478

American (AMR)

AF:

0.0359

AC:

1607

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.0137

AC:

542

AN:

39680

South Asian (SAS)

AF:

0.000185

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00384

AC:

205

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

1111962

Other (OTH)

AF:

0.00189

AC:

114

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

152

305

457

610

762

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.00274

AC:

417

AN:

152224

Hom.:

Cov.:

AF XY:

0.00316

AC XY:

235

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41538

American (AMR)

AF:

0.0153

AC:

234

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0122

AC:

AN:

5172

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00774

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68012

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00116

Hom.:

Bravo

AF:

0.00479

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00525

AC:

637

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital ichthyosis of skin (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.34

CADD

Benign

8.4

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.10

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0033

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.5

PhyloP100

0.52

PrimateAI

Benign

0.18

PROVEAN

Benign

-0.66

REVEL

Benign

0.14

Sift

Benign

0.20

Sift4G

Uncertain

0.024

Polyphen

0.41

Vest4

0.23

MVP

0.66

MPC

0.26

ClinPred

0.0024

GERP RS

2.4

Varity_R

0.024

gMVP

0.34

Mutation Taster

=98/2

polymorphism (auto)

(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.

rs76979001

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over