7-48193020-G-A

Variant names:

• chr7-48193020-G-A
• rs566894266
• NM_152701.5:c.131G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_152701.5(ABCA13):​c.131G>A​(p.Arg44His) variant causes a missense change. The variant allele was found at a frequency of 0.0000301 in 1,527,832 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (1 hom.)
• Consequence: ABCA13 NM_152701.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.10
• Publications: 0 publications found

Genes affected

ABCA13 (HGNC:14638): (ATP binding cassette subfamily A member 13) In human, the ATP-binding cassette (ABC) family of transmembrane transporters has at least 48 genes and 7 gene subfamilies. This gene is a member of ABC gene subfamily A (ABCA). Genes within the ABCA family typically encode several thousand amino acids. Like other ABC transmembrane transporter proteins, this protein has 12 or more transmembrane alpha-helix domains that likely arrange to form a single central chamber with multiple substrate binding sites. It is also predicted to have two large extracellular domains and two nucleotide binding domains as is typical for ABCA proteins. Alternative splice variants have been described but their biological validity has not been demonstrated.[provided by RefSeq, Mar 2009]

ABCA13 Gene-Disease associations (from GenCC):

• schizophrenia

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCA13	NM_152701.5	c.131G>A	p.Arg44His	missense_variant	Exon 2 of 62	ENST00000435803.6	NP_689914.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCA13	ENST00000435803.6	c.131G>A	p.Arg44His	missense_variant	Exon 2 of 62	1	NM_152701.5	ENSP00000411096.1
ABCA13	ENST00000417403.5	n.131G>A		non_coding_transcript_exon_variant	Exon 2 of 18	2		ENSP00000409268.1

Frequencies

GnomAD3 genomes AF: 0.0000336 AC: 5 AN: 148698 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000202

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000795 AC: 11 AN: 138436 AF XY: 0.0000809

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000248

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000305 AC: 42 AN: 1379032 Hom.: 1 Cov.: 31 AF XY: 0.0000338 AC XY: 23 AN XY: 680266

African (AFR) AF: 0.00 AC: 0 AN: 31296

American (AMR) AF: 0.000198 AC: 7 AN: 35314

Ashkenazi Jewish (ASJ) AF: 0.000120 AC: 3 AN: 25002

East Asian (EAS) AF: 0.00 AC: 0 AN: 35316

South Asian (SAS) AF: 0.000167 AC: 13 AN: 78058

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34872

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5680

European-Non Finnish (NFE) AF: 0.0000130 AC: 14 AN: 1075842

Other (OTH) AF: 0.0000694 AC: 4 AN: 57652

GnomAD4 genome AF: 0.0000269 AC: 4 AN: 148800 Hom.: 0 Cov.: 32 AF XY: 0.0000553 AC XY: 4 AN XY: 72270

African (AFR) AF: 0.00 AC: 0 AN: 40332

American (AMR) AF: 0.000202 AC: 3 AN: 14886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5078

South Asian (SAS) AF: 0.00 AC: 0 AN: 4736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67472

Other (OTH) AF: 0.00 AC: 0 AN: 2056

Alfa AF: 0.0000359 Hom.: 0

Bravo AF: 0.0000680

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 19, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.131G>A (p.R44H) alteration is located in exon 2 (coding exon 2) of the ABCA13 gene. This alteration results from a G to A substitution at nucleotide position 131, causing the arginine (R) at amino acid position 44 to be replaced by a histidine (H). 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	Uncertain	0.50
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	28
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		5.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.72
MutPred		0.55		Gain of catalytic residue at L43 (P = 0.1593);
MVP		0.93
MPC		0.22
ClinPred		0.87	D
GERP RS		5.3
gMVP		0.62
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs566894266; hg19: chr7-48232617; COSMIC: COSV70040197;