22-21029905-C-G

Variant names:

• chr22-21029905-C-G
• rs1928823828
• NM_004173.3:c.1429G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004173.3(SLC7A4):​c.1429G>C​(p.Val477Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLC7A4 NM_004173.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.95

Genes affected

SLC7A4 (HGNC:11062): (solute carrier family 7 member 4) Predicted to enable amino acid transmembrane transporter activity. Predicted to be involved in amino acid transport. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000291240 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15203372).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC7A4	NM_004173.3	c.1429G>C	p.Val477Leu	missense_variant	Exon 3 of 5	ENST00000382932.3	NP_004164.2
SLC7A4	XM_047441472.1	c.1429G>C	p.Val477Leu	missense_variant	Exon 2 of 4		XP_047297428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC7A4	ENST00000382932.3	c.1429G>C	p.Val477Leu	missense_variant	Exon 3 of 5	1	NM_004173.3	ENSP00000372390.2
SLC7A4	ENST00000403586.5	c.1429G>C	p.Val477Leu	missense_variant	Exon 3 of 5	1		ENSP00000384278.1
ENSG00000291240	ENST00000706202.1	n.1429G>C		non_coding_transcript_exon_variant	Exon 3 of 7			ENSP00000516280.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461560 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727082

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1429G>C (p.V477L) alteration is located in exon 3 (coding exon 2) of the SLC7A4 gene. This alteration results from a G to C substitution at nucleotide position 1429, causing the valine (V) at amino acid position 477 to be replaced by a leucine (L). 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	Benign	0.16
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	11
DANN	Benign	0.72
DEOGEN2	Benign	0.028	T;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.61
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.69	.;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.5	L;L
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.15
Sift	Benign	0.16	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.015	B;B
Vest4		0.046
MutPred		0.44		Loss of catalytic residue at V477 (P = 0.0682);Loss of catalytic residue at V477 (P = 0.0682);
MVP		0.40
MPC		0.084
ClinPred		0.92	D
GERP RS		0.87
Varity_R		0.089
gMVP		0.53

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: rs1928823828; hg19: chr22-21384194;