2-44275766-T-A

Position:

• chr2-44275766-T-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6 BP7 BS2_Supporting

The NM_000341.4(SLC3A1):​c.231T>A​(p.Ser77Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00327 in 1,614,254 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (11 hom.)
• Consequence: SLC3A1 NM_000341.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -4.31

Genes affected

SLC3A1 (HGNC:11025): (solute carrier family 3 member 1) This gene encodes a type II membrane glycoprotein which is one of the components of the renal amino acid transporter which transports neutral and basic amino acids in the renal tubule and intestinal tract. Mutations and deletions in this gene are associated with cystinuria. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

ENSG00000285542 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-44275766-T-A is Benign according to our data. Variant chr2-44275766-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 526034.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=2}. Variant chr2-44275766-T-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.31 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 11 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC3A1	NM_000341.4	c.231T>A	p.Ser77Ser	synonymous_variant	1/10	ENST00000260649.11	NP_000332.2
SLC3A1	XM_011533047.4	c.231T>A	p.Ser77Ser	synonymous_variant	1/10		XP_011531349.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC3A1	ENST00000260649.11	c.231T>A	p.Ser77Ser	synonymous_variant	1/10	1	NM_000341.4	ENSP00000260649.6
ENSG00000285542	ENST00000649044.1	n.*242T>A		non_coding_transcript_exon_variant	6/15			ENSP00000497083.1
ENSG00000285542	ENST00000649044.1	n.*242T>A		3_prime_UTR_variant	6/15			ENSP00000497083.1

Frequencies

GnomAD3 genomes AF: 0.00247 AC: 376 AN: 152246 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00363

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00256 AC: 643 AN: 251402 Hom.: 4 AF XY: 0.00274 AC XY: 372 AN XY: 135890

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00516

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.000970

Gnomad NFE exome AF: 0.00436

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00335 AC: 4904 AN: 1461892 Hom.: 11 Cov.: 34 AF XY: 0.00326 AC XY: 2369 AN XY: 727248

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000984

Gnomad4 ASJ exome AF: 0.00559

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.00148

Gnomad4 NFE exome AF: 0.00395

Gnomad4 OTH exome AF: 0.00300

GnomAD4 genome AF: 0.00247 AC: 377 AN: 152362 Hom.: 1 Cov.: 33 AF XY: 0.00256 AC XY: 191 AN XY: 74510

Gnomad4 AFR AF: 0.000721

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00363

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00323 Hom.: 0

Bravo AF: 0.00233

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00414

EpiControl AF: 0.00403

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SLC3A1: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Cystinuria Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.039
DANN	Benign	0.80

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: rs146630359; hg19: chr2-44502905;