rs149399707

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_173076.3(ABCA12):c.485C>T(p.Ala162Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,612,514 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A162P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 7 hom. )

Consequence

ABCA12
NM_173076.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: 1.32

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: G2P, Genomics England PanelApp, Orphanet
autosomal recessive congenital ichthyosis 4A
Inheritance: AR Classification: STRONG Submitted by: 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013969272).

BP6

Variant 2-215052509-G-A is Benign according to our data. Variant chr2-215052509-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235587.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00124 (189/152140) while in subpopulation NFE AF = 0.00219 (149/67978). AF 95% confidence interval is 0.0019. There are 0 homozygotes in GnomAd4. There are 77 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 7 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABCA12	NM_173076.3	MANE Select	c.485C>T	p.Ala162Val	missense	Exon 5 of 53	NP_775099.2
	ABCA12	NR_103740.2		n.903C>T		non_coding_transcript_exon	Exon 5 of 55

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ABCA12	ENST00000272895.12	TSL:1 MANE Select	c.485C>T	p.Ala162Val	missense	Exon 5 of 53	ENSP00000272895.7	Q86UK0-1
ENSG00000227769	ENST00000626134.2	TSL:5	n.404+7992G>A		intron	N/A
ENSG00000227769	ENST00000626771.1	TSL:5	n.338+7992G>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00124

AC:

189

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00158

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00219

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.00139

AC:

349

AN:

250822

AF XY:

0.00151

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00222

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00156

AC:

2274

AN:

1460374

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

1132

AN XY:

726510

show subpopulations

African (AFR)

AF:

0.0000898

AC:

AN:

33400

American (AMR)

AF:

0.00107

AC:

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26056

East Asian (EAS)

AF:

0.00

AC:

AN:

39652

South Asian (SAS)

AF:

0.00157

AC:

135

AN:

86232

European-Finnish (FIN)

AF:

0.000337

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00177

AC:

1970

AN:

1110954

Other (OTH)

AF:

0.00154

AC:

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

113

226

340

453

566

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

204

272

340

<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:

0.00124

AC:

189

AN:

152140

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41538

American (AMR)

AF:

0.00157

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000830

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00219

AC:

149

AN:

67978

Other (OTH)

AF:

0.000475

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00173

Hom.:

Bravo

AF:

0.00140

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.00140

AC:

170

EpiCase

AF:

0.00196

EpiControl

AF:

0.00267

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

ABCA12-related disorder (1)

Autosomal recessive congenital ichthyosis 4B (1)

Congenital ichthyosis of skin (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.078

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.75

M_CAP

Benign

0.032

MetaRNN

Benign

0.014

MetaSVM

Benign

-0.61

MutationAssessor

Benign

0.69

PhyloP100

1.3

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.50

REVEL

Benign

0.15

Sift

Benign

0.16

Sift4G

Benign

0.093

Polyphen

0.047

Vest4

0.39

MVP

0.69

MPC

0.19

ClinPred

0.011

GERP RS

3.7

Varity_R

0.064

gMVP

0.36

Mutation Taster

=96/4

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over