rs11890468

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_173076.3(ABCA12):c.821A>G(p.Gln274Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00657 in 1,613,578 control chromosomes in the GnomAD database, including 570 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.035 ( 294 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 276 hom. )

Consequence

ABCA12
NM_173076.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.43

Publications

10 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=0.0015814602).

BP6

Variant 2-215045888-T-C is Benign according to our data. Variant chr2-215045888-T-C is described in ClinVar as Benign. ClinVar VariationId is 235321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA12	NM_173076.3 link	c.821A>G	p.Gln274Arg	missense_variant	Exon 7 of 53	ENST00000272895.12	NP_775099.2	Q86UK0-1B3KVV3
ABCA12	XM_011510951.3 link	c.821A>G	p.Gln274Arg	missense_variant	Exon 7 of 53		XP_011509253.1
ABCA12	NR_103740.2 link	n.1263A>G		non_coding_transcript_exon_variant	Exon 8 of 55

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ABCA12	ENST00000272895.12 link	c.821A>G	p.Gln274Arg	missense_variant	Exon 7 of 53	1	NM_173076.3	ENSP00000272895.7	Q86UK0-1
ENSG00000227769	ENST00000626134.2 link	n.404+1371T>C		intron_variant	Intron 4 of 4	5
ENSG00000227769	ENST00000626771.1 link	n.338+1371T>C		intron_variant	Intron 4 of 5	5
ENSG00000227769	ENST00000628464.2 link	n.1021+1371T>C		intron_variant	Intron 7 of 8	5

Frequencies

GnomAD3 genomes

AF:

0.0349

AC:

5313

AN:

152166

Hom.:

292

Cov.:

show subpopulations

Gnomad AFR

AF:

0.119

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0171

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.0310

GnomAD2 exomes

AF:

0.00923

AC:

2312

AN:

250430

AF XY:

0.00672

show subpopulations

Gnomad AFR exome

AF:

0.124

Gnomad AMR exome

AF:

0.00598

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000433

Gnomad OTH exome

AF:

0.00623

GnomAD4 exome

AF:

0.00361

AC:

5269

AN:

1461294

Hom.:

276

Cov.:

AF XY:

0.00304

AC XY:

2213

AN XY:

726960

show subpopulations

African (AFR)

AF:

0.120

AC:

4023

AN:

33388

American (AMR)

AF:

0.00759

AC:

339

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.000244

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53304

Middle Eastern (MID)

AF:

0.00746

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000305

AC:

339

AN:

1111754

Other (OTH)

AF:

0.00835

AC:

504

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

225

450

675

900

1125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

130

260

390

520

650

<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:

0.0350

AC:

5327

AN:

152284

Hom.:

294

Cov.:

AF XY:

0.0334

AC XY:

2489

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.119

AC:

4959

AN:

41548

American (AMR)

AF:

0.0171

AC:

261

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000588

AC:

AN:

68022

Other (OTH)

AF:

0.0307

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

242

485

727

970

1212

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0126

Hom.:

192

Bravo

AF:

0.0414

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.126

AC:

557

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.0117

AC:

1423

Asia WGS

AF:

0.00779

AC:

AN:

3478

EpiCase

AF:

0.000655

EpiControl

AF:

0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 22, 2015

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: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

0.073

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.55

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PhyloP100

1.4

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.81

REVEL

Benign

0.031

Sift

Benign

0.072

Sift4G

Uncertain

0.018

Polyphen

0.0010

Vest4

0.050

MPC

0.20

ClinPred

0.0049

GERP RS

3.2

Varity_R

0.11

gMVP

0.42

Mutation Taster

=96/4

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

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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