22-32221001-G-T

Variant names:

• chr22-32221001-G-T
• rs1925046647
• NM_014227.3:c.1687C>A

Variant summary

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

The NM_014227.3(SLC5A4):​c.1687C>A​(p.Leu563Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC5A4 NM_014227.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.08

Genes affected

SLC5A4 (HGNC:11039): (solute carrier family 5 member 4) Predicted to enable glucose:sodium symporter activity and proton transmembrane transporter activity. Predicted to be involved in sodium ion transport. Predicted to act upstream of or within proton transmembrane transport. Predicted to be active in plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

SLC5A4-AS1 (HGNC:53163): (SLC5A4 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC5A4	NM_014227.3	c.1687C>A	p.Leu563Ile	missense_variant	Exon 14 of 15	ENST00000266086.6	NP_055042.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC5A4	ENST00000266086.6	c.1687C>A	p.Leu563Ile	missense_variant	Exon 14 of 15	1	NM_014227.3	ENSP00000266086.3
SLC5A4-AS1	ENST00000434942.2	n.225-8089G>T		intron_variant	Intron 2 of 4	3
SLC5A4-AS1	ENST00000452181.2	n.274+13725G>T		intron_variant	Intron 2 of 4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1687C>A (p.L563I) alteration is located in exon 14 (coding exon 14) of the SLC5A4 gene. This alteration results from a C to A substitution at nucleotide position 1687, causing the leucine (L) at amino acid position 563 to be replaced by an isoleucine (I). 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	0.22
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.6	H
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.53
Sift	Benign	0.19	T
Sift4G	Benign	0.36	T
Polyphen		0.94	P
Vest4		0.58
MutPred		0.37		Loss of helix (P = 0.1299);
MVP		0.55
MPC		0.70
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.16
gMVP		0.27

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: rs1925046647; hg19: chr22-32616988; COSMIC: COSV56669468;