3-170467150-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020949.3(SLC7A14):c.2221G>A(p.Gly741Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,614,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G741G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: SLC7A14 NM_020949.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.724

Genes affected

SLC7A14 (HGNC:29326): (solute carrier family 7 member 14) This gene is predicted to encode a glycosylated, cationic amino acid transporter protein with 14 transmembrane domains. This gene is primarily expressed in skin fibroblasts, neural tissue, and primary endothelial cells and its protein is predicted to mediate lysosomal uptake of cationic amino acids. Mutations in this gene are associated with autosomal recessive retinitis pigmentosa. In mice, this gene is expressed in the photoreceptor layer of the retina where its expression increases over the course of retinal development and persists in the mature retina. [provided by RefSeq, Apr 2014]

SLC7A14-AS1 (HGNC:54092): (SLC7A14 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.020714194).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC7A14	NM_020949.3	c.2221G>A	p.Gly741Ser	missense_variant	8/8	ENST00000231706.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC7A14	ENST00000231706.6	c.2221G>A	p.Gly741Ser	missense_variant	8/8	2	NM_020949.3	P1
SLC7A14-AS1	ENST00000643719.1	n.273+6738C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152258 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000964

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251348 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000497

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74378

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000172 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 01, 2023

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 741 of the SLC7A14 protein (p.Gly741Ser). This variant is present in population databases (rs773800039, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with SLC7A14-related conditions. ClinVar contains an entry for this variant (Variation ID: 1423081). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	9.8
Dann	Benign	0.79
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	-0.90	N
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.20	N
REVEL	Uncertain	0.31
Sift	Benign	1.0	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.026
MutPred		0.13		Gain of phosphorylation at G741 (P = 0.0168);
MVP		0.11
MPC		0.14
ClinPred		0.058	T
GERP RS		-3.2
Varity_R		0.040
gMVP		0.15

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: rs773800039; hg19: chr3-170184938;