2-127701872-G-T

Variant names:

• chr2-127701872-G-T
• rs780314092
• NM_032740.4:c.344G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_032740.4(SFT2D3):​c.344G>T​(p.Gly115Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000993 in 1,308,882 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000099 (0 hom.)
• Consequence: SFT2D3 NM_032740.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.46

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 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, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFT2D3	NM_032740.4	c.344G>T	p.Gly115Val	missense_variant	Exon 1 of 1	ENST00000310981.6	NP_116129.3
WDR33	NM_018383.5	c.*4451C>A		3_prime_UTR_variant	Exon 22 of 22	ENST00000322313.9	NP_060853.3
WDR33	XM_011511436.2	c.*4451C>A		3_prime_UTR_variant	Exon 22 of 22		XP_011509738.1
WDR33	XM_005263697.4	c.*4621C>A		3_prime_UTR_variant	Exon 21 of 21		XP_005263754.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFT2D3	ENST00000310981.6	c.344G>T	p.Gly115Val	missense_variant	Exon 1 of 1	6	NM_032740.4	ENSP00000310803.3
WDR33	ENST00000322313	c.*4451C>A		3_prime_UTR_variant	Exon 22 of 22	1	NM_018383.5	ENSP00000325377.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.000145 AC: 11 AN: 75816 Hom.: 0 AF XY: 0.0000910 AC XY: 4 AN XY: 43932

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000769

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000993 AC: 13 AN: 1308882 Hom.: 0 Cov.: 31 AF XY: 0.00000619 AC XY: 4 AN XY: 645930

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000513

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000264

ExAC AF: 0.0000292 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 26, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.344G>T (p.G115V) alteration is located in exon 1 (coding exon 1) of the SFT2D3 gene. This alteration results from a G to T substitution at nucleotide position 344, causing the glycine (G) at amino acid position 115 to be replaced by a valine (V). 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	0.90
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	3.6	H
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-8.7	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.93		Gain of MoRF binding (P = 0.0887);
MVP		0.85
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.95
gMVP		0.81

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: rs780314092; hg19: chr2-128459446;