7-48171493-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_152701.5(ABCA13):c.10G>A(p.Ala4Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000309 in 1,536,154 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: ABCA13 NM_152701.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.422

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.019642651).
• BP6: Variant 7-48171493-G-A is Benign according to our data. Variant chr7-48171493-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2458275.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA13	NM_152701.5	c.10G>A	p.Ala4Thr	missense_variant	1/62	ENST00000435803.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA13	ENST00000435803.6	c.10G>A	p.Ala4Thr	missense_variant	1/62	1	NM_152701.5	P1
ABCA13	ENST00000417403.5	c.10G>A	p.Ala4Thr	missense_variant, NMD_transcript_variant	1/18	2

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000198 AC: 28 AN: 141750 Hom.: 0 AF XY: 0.000158 AC XY: 12 AN XY: 75814

Gnomad AFR exome AF: 0.000264

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000447

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000306 AC: 424 AN: 1383820 Hom.: 1 Cov.: 30 AF XY: 0.000290 AC XY: 198 AN XY: 682844

Gnomad4 AFR exome AF: 0.0000950

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000380

Gnomad4 OTH exome AF: 0.000173

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74486

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000661

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000427 Hom.: 0

Bravo AF: 0.000302

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.000314 AC: 1

ExAC AF: 0.0000481 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2023

The c.10G>A (p.A4T) alteration is located in exon 1 (coding exon 1) of the ABCA13 gene. This alteration results from a G to A substitution at nucleotide position 10, causing the alanine (A) at amino acid position 4 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

ABCA13: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	1.5
Dann	Benign	0.86
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.75	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.11
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.032	D
Vest4		0.15
MVP		0.20
MPC		0.035
ClinPred		0.0082	T
GERP RS		-2.6
gMVP		0.12

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

LitVar

Other links and lift over

dbSNP: rs144916268; hg19: chr7-48211090;