7-20628718-C-A

Variant names:

• chr7-20628718-C-A
• rs569259461
• NM_001163941.2:c.139C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001163941.2(ABCB5):​c.139C>A​(p.Leu47Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,613,310 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L47P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: ABCB5 NM_001163941.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.24
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB5	NM_001163941.2	c.139C>A	p.Leu47Ile	missense_variant	Exon 4 of 28	ENST00000404938.7	NP_001157413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB5	ENST00000404938.7	c.139C>A	p.Leu47Ile	missense_variant	Exon 4 of 28	1	NM_001163941.2	ENSP00000384881.2

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 152004 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000202 AC: 5 AN: 248134 AF XY: 0.0000297

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000356

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000479 AC: 70 AN: 1461306 Hom.: 0 Cov.: 32 AF XY: 0.0000440 AC XY: 32 AN XY: 726898

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.0000594 AC: 66 AN: 1111716

Other (OTH) AF: 0.0000497 AC: 3 AN: 60352

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 152004 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 5 AN XY: 74236

African (AFR) AF: 0.0000483 AC: 2 AN: 41384

American (AMR) AF: 0.00 AC: 0 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000711 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000249 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.0000595

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 31, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.139C>A (p.L47I) alteration is located in exon 4 (coding exon 3) of the ABCB5 gene. This alteration results from a C to A substitution at nucleotide position 139, causing the leucine (L) at amino acid position 47 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.061	T
Eigen	Benign	0.19
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.087	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	-0.24	T
PhyloP100		2.2
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.99	N
REVEL	Uncertain	0.35
Sift	Benign	0.057	T
Sift4G	Uncertain	0.018	D
Vest4		0.52
MVP		0.81
MPC		0.038
ClinPred		0.64	D
GERP RS		4.3
Varity_R		0.24
gMVP		0.18
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs569259461; hg19: chr7-20668341;