Variant chr2-127701776-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_032740.4(SFT2D3):c.248G>A(p.Cys83Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000168 in 1,429,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

SFT2D3
NM_032740.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.39

Variant links:

Genes affected

SFT2D3 (HGNC:28767): (SFT2 domain containing 3) Predicted to be involved in protein transport and vesicle-mediated transport. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

SFT2D3 links:

WDR33 (HGNC:25651): (WD repeat domain 33) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. This gene is highly expressed in testis and the protein is localized to the nucleus. This gene may play important roles in the mechanisms of cytodifferentiation and/or DNA recombination. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

WDR33 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SFT2D3	NM_032740.4 link	c.248G>A	p.Cys83Tyr	missense_variant	1/1	ENST00000310981.6	NP_116129.3	Q587I9
WDR33	NM_018383.5 link	c.*4547C>T		3_prime_UTR_variant	22/22	ENST00000322313.9	NP_060853.3	Q9C0J8-1
WDR33	XM_011511436.2 link	c.*4547C>T		3_prime_UTR_variant	22/22		XP_011509738.1	Q9C0J8-1
WDR33	XM_005263697.4 link	c.*4717C>T		3_prime_UTR_variant	21/21		XP_005263754.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SFT2D3	ENST00000310981.6 link	c.248G>A	p.Cys83Tyr	missense_variant	1/1	6	NM_032740.4	ENSP00000310803.3		Q587I9
WDR33	ENST00000322313 link	c.*4547C>T		3_prime_UTR_variant	22/22	1	NM_018383.5	ENSP00000325377.3		Q9C0J8-1

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

150584

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000172

AC:

AN:

1279346

Hom.:

Cov.:

AF XY:

0.0000143

AC XY:

AN XY:

630924

show subpopulations

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:

0.0000215

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000133

AC:

AN:

150584

Hom.:

Cov.:

AF XY:

0.0000272

AC XY:

AN XY:

73444

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000149

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2024

The c.248G>A (p.C83Y) alteration is located in exon 1 (coding exon 1) of the SFT2D3 gene. This alteration results from a G to A substitution at nucleotide position 248, causing the cysteine (C) at amino acid position 83 to be replaced by a tyrosine (Y). 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

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.54

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

-0.25

MutationAssessor

Uncertain

2.3

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-9.4

REVEL

Uncertain

0.47

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.61

MutPred

0.92

Loss of catalytic residue at L84 (P = 0.041);

MVP

0.58

ClinPred

0.74

GERP RS

3.9

Varity_R

0.96

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over