1-234318853-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_173508.4(SLC35F3):c.1057A>G(p.Ile353Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,840 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC35F3 NM_173508.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.52

Genes affected

SLC35F3 (HGNC:23616): (solute carrier family 35 member F3) Involved in thiamine transport. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05270058).
• BP6: Variant 1-234318853-A-G is Benign according to our data. Variant chr1-234318853-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2335965.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC35F3	NM_173508.4	c.1057A>G	p.Ile353Val	missense_variant	6/8	ENST00000366618.8
SLC35F3	NM_001300845.2	c.850A>G	p.Ile284Val	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC35F3	ENST00000366618.8	c.1057A>G	p.Ile353Val	missense_variant	6/8	2	NM_173508.4
SLC35F3	ENST00000366617.3	c.850A>G	p.Ile284Val	missense_variant	5/7	1		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461840 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727226

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	10
Dann	Benign	0.44
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.053	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.92	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.50	N;N
REVEL	Benign	0.090
Sift	Benign	0.75	T;T
Sift4G	Benign	0.86	T;T
Polyphen		0.0	B;B
Vest4		0.12
MutPred		0.40		.;Gain of catalytic residue at I284 (P = 0.1176);
MVP		0.043
MPC		0.50
ClinPred		0.20	T
GERP RS		3.5
Varity_R		0.030
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs955692073; hg19: chr1-234454599;