22-32218605-G-A

Variant names:

• chr22-32218605-G-A
• rs956255284
• NM_014227.3:c.1889C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014227.3(SLC5A4):​c.1889C>T​(p.Thr630Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T630R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC5A4 NM_014227.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.25
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38870373).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014227.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC5A4	NM_014227.3	MANE Select	c.1889C>T	p.Thr630Met	missense	Exon 15 of 15	NP_055042.1	Q9NY91
	SLC5A4-AS1	NR_149072.1		n.274+11329G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC5A4	ENST00000266086.6	TSL:1 MANE Select	c.1889C>T	p.Thr630Met	missense	Exon 15 of 15	ENSP00000266086.3	Q9NY91
	SLC5A4-AS1	ENST00000434942.2	TSL:3	n.225-10485G>A		intron	N/A
	SLC5A4-AS1	ENST00000452181.2	TSL:5	n.274+11329G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251490 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461248 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726952

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111416

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	18
DANN	Benign	0.78
DEOGEN2	Benign	0.0084	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	-0.060	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		4.2
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.43
Sift	Benign	0.036	D
Sift4G	Benign	0.088	T
Polyphen		0.28	B
Vest4		0.62
MutPred		0.17		Gain of loop (P = 0.0312)
MVP		0.49
MPC		0.62
ClinPred		0.53	D
GERP RS		3.2
Varity_R		0.041
gMVP		0.31
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs956255284; hg19: chr22-32614592;