chr2-127701687-G-C

Position:

• chr2-127701687-G-C

Variant summary

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

The NM_032740.4(SFT2D3):​c.159G>C​(p.Trp53Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000401 in 1,147,130 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: SFT2D3 NM_032740.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74

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]

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]

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/exons	MANE	Protein	UniProt
SFT2D3	NM_032740.4	c.159G>C	p.Trp53Cys	missense_variant	1/1	ENST00000310981.6	NP_116129.3
WDR33	NM_018383.5	c.*4636C>G		3_prime_UTR_variant	22/22	ENST00000322313.9	NP_060853.3
WDR33	XM_011511436.2	c.*4636C>G		3_prime_UTR_variant	22/22		XP_011509738.1
WDR33	XM_005263697.4	c.*4806C>G		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	c.159G>C	p.Trp53Cys	missense_variant	1/1	6	NM_032740.4	ENSP00000310803.3
WDR33	ENST00000322313	c.*4636C>G		3_prime_UTR_variant	22/22	1	NM_018383.5	ENSP00000325377.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000401 AC: 46 AN: 1147130 Hom.: 0 Cov.: 31 AF XY: 0.0000396 AC XY: 22 AN XY: 555282

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: 0.0000468

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 2024

The c.159G>C (p.W53C) alteration is located in exon 1 (coding exon 1) of the SFT2D3 gene. This alteration results from a G to C substitution at nucleotide position 159, causing the tryptophan (W) at amino acid position 53 to be replaced by a cysteine (C). 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	0.63
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.064	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.073
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.73	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.15
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.010	D
Polyphen		0.96	D
Vest4		0.34
MutPred		0.38		Loss of MoRF binding (P = 0.0287);
MVP		0.48
ClinPred		0.99	D
GERP RS		3.7
Varity_R		0.69
gMVP		0.59

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: rs953675687; hg19: chr2-128459261;