chr17-69253570-C-T

Position:

• chr17-69253570-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The ENST00000392676.8(ABCA5):​c.4415+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,604,852 control chromosomes in the GnomAD database, including 360 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.012 (23 hom., cov: 32)
  • Exomes 𝑓: 0.019 (337 hom.)
• Consequence: ABCA5 ENST00000392676.8 splice_region, intron
• Scores: Splicing: ADA: 0.00006409
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.291

Genes affected

ABCA5 (HGNC:35): (ATP binding cassette subfamily A member 5) 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. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. This gene is clustered among 4 other ABC1 family members on 17q24, but neither the substrate nor the function of this gene is known. Alternative splicing of this gene results in several transcript variants; however, not all variants have been fully described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 17-69253570-C-T is Benign according to our data. Variant chr17-69253570-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3037281.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0119 (1816/152262) while in subpopulation NFE AF= 0.0212 (1443/67998). AF 95% confidence interval is 0.0203. There are 23 homozygotes in gnomad4. There are 785 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCA5	NM_172232.4	c.4415+3G>A		splice_region_variant, intron_variant		ENST00000392676.8	NP_758424.1
ABCA5	NM_018672.5	c.4415+3G>A		splice_region_variant, intron_variant			NP_061142.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCA5	ENST00000392676.8	c.4415+3G>A		splice_region_variant, intron_variant		1	NM_172232.4	ENSP00000376443.2

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1816 AN: 152144 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00449

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00831

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00349

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0212

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.0107 AC: 2692 AN: 250930 Hom.: 39 AF XY: 0.0110 AC XY: 1490 AN XY: 135612

Gnomad AFR exome AF: 0.00375

Gnomad AMR exome AF: 0.00448

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00134

Gnomad FIN exome AF: 0.00527

Gnomad NFE exome AF: 0.0198

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0193 AC: 28032 AN: 1452590 Hom.: 337 Cov.: 29 AF XY: 0.0186 AC XY: 13427 AN XY: 723364

Gnomad4 AFR exome AF: 0.00279

Gnomad4 AMR exome AF: 0.00503

Gnomad4 ASJ exome AF: 0.000154

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00115

Gnomad4 FIN exome AF: 0.00659

Gnomad4 NFE exome AF: 0.0238

Gnomad4 OTH exome AF: 0.0163

GnomAD4 genome AF: 0.0119 AC: 1816 AN: 152262 Hom.: 23 Cov.: 32 AF XY: 0.0105 AC XY: 785 AN XY: 74440

Gnomad4 AFR AF: 0.00448

Gnomad4 AMR AF: 0.00830

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00349

Gnomad4 NFE AF: 0.0212

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.0167 Hom.: 22

Bravo AF: 0.0126

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0199

EpiControl AF: 0.0179

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ABCA5-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 06, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	11
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000064
dbscSNV1_RF	Benign	0.0
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: rs77262773; hg19: chr17-67249711;