Genetic Variant NM_001163941.2:c.463T>G (chr7-20643332-T-G) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2PP3BP4_Strong

The NM_001163941.2(ABCB5):c.463T>G(p.Phe155Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0013 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ABCB5
NM_001163941.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.82

Publications

5 publications found

Variant links:

Genes affected

ABCB5 (HGNC:46): (ATP binding cassette subfamily B member 5) ABCB5 belongs to the ATP-binding cassette (ABC) transporter superfamily of integral membrane proteins. These proteins participate in ATP-dependent transmembrane transport of structurally diverse molecules ranging from small ions, sugars, and peptides to more complex organic molecules (Chen et al., 2005 [PubMed 15760339]).[supplied by OMIM, Mar 2008]

ABCB5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Multiple lines of computational evidence support a deleterious effect 6: BayesDel_addAF, Cadd, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.024998426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB5	NM_001163941.2 link	c.463T>G	p.Phe155Val	missense_variant	Exon 6 of 28	ENST00000404938.7	NP_001157413.1	Q2M3G0-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB5	ENST00000404938.7 link	c.463T>G	p.Phe155Val	missense_variant	Exon 6 of 28	1	NM_001163941.2	ENSP00000384881.2		Q2M3G0-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0104

AC:

2475

AN:

239010

AF XY:

0.00786

show subpopulations

Gnomad AFR exome

AF:

0.0256

Gnomad AMR exome

AF:

0.00939

Gnomad ASJ exome

AF:

0.00283

Gnomad EAS exome

AF:

0.00983

Gnomad FIN exome

AF:

0.0101

Gnomad NFE exome

AF:

0.0123

Gnomad OTH exome

AF:

0.00552

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00128

AC:

1858

AN:

1456464

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

924

AN XY:

724342

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00249

AC:

AN:

33278

American (AMR)

AF:

0.0118

AC:

514

AN:

43388

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00685

AC:

268

AN:

39134

South Asian (SAS)

AF:

0.000372

AC:

AN:

86052

European-Finnish (FIN)

AF:

0.00935

AC:

488

AN:

52198

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000375

AC:

416

AN:

1110424

Other (OTH)

AF:

0.000932

AC:

AN:

60116

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.306

Heterozygous variant carriers

132

264

396

528

660

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

114

152

190

<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

Cov.:

Alfa

AF:

0.00000505

Hom.:

ExAC

AF:

0.0273

AC:

3292

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.025

MetaSVM

Uncertain

0.72

PhyloP100

7.8

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.86

Sift

Uncertain

0.015

Sift4G

Uncertain

0.019

Vest4

0.30

MPC

0.038

ClinPred

0.027

GERP RS

3.8

Varity_R

0.76

gMVP

0.64

Mutation Taster

=42/58

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over