6-8419675-C-T

Variant names:

• chr6-8419675-C-T
• rs901366430
• NM_001370476.2:c.685G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001370476.2(SLC35B3):​c.685G>A​(p.Val229Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000681 in 1,497,406 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: SLC35B3 NM_001370476.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.69
• Publications: 0 publications found

Genes affected

SLC35B3 (HGNC:21601): (solute carrier family 35 member B3) This gene is a member of the solute carrier family. The encoded protein is involved in the transport of 3-prime phosphoadenosine 5-prime phosphosulfate (PAPS) from the nucleus or the cytosol to the Golgi lumen. This gene has been reported to be expressed preferentially in the human colon tissues. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

ENSG00000285216 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 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
SLC35B3	NM_001370476.2	c.685G>A	p.Val229Met	missense_variant, splice_region_variant	Exon 7 of 11	ENST00000644923.2	NP_001357405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC35B3	ENST00000644923.2	c.685G>A	p.Val229Met	missense_variant, splice_region_variant	Exon 7 of 11		NM_001370476.2	ENSP00000496368.1
SLC35B3	ENST00000710437.1	c.589G>A	p.Val197Met	missense_variant, splice_region_variant	Exon 6 of 10			ENSP00000518269.1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152030 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000883

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000280 AC: 6 AN: 214400 AF XY: 0.0000343

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000588

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000714 AC: 96 AN: 1345376 Hom.: 0 Cov.: 24 AF XY: 0.0000691 AC XY: 46 AN XY: 665662

African (AFR) AF: 0.00 AC: 0 AN: 30008

American (AMR) AF: 0.00 AC: 0 AN: 35356

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23328

East Asian (EAS) AF: 0.00 AC: 0 AN: 36558

South Asian (SAS) AF: 0.00 AC: 0 AN: 69048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5338

European-Non Finnish (NFE) AF: 0.0000912 AC: 95 AN: 1041274

Other (OTH) AF: 0.0000183 AC: 1 AN: 54620

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152030 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74252

African (AFR) AF: 0.00 AC: 0 AN: 41402

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67958

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000824 Hom.: 0

Bravo AF: 0.0000491

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.685G>A (p.V229M) alteration is located in exon 7 (coding exon 6) of the SLC35B3 gene. This alteration results from a G to A substitution at nucleotide position 685, causing the valine (V) at amino acid position 229 to be replaced by a methionine (M). 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	0.29
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.062	.;T;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.6	.;M;M
PhyloP100		7.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.3	.;N;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	.;D;.
Sift4G	Uncertain	0.0050	.;D;.
Polyphen		0.96	.;D;D
Vest4		0.90
MVP		0.52
MPC		0.48
ClinPred		0.78	D
GERP RS		5.4
Varity_R		0.53
gMVP		0.61
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs901366430; hg19: chr6-8419908;