chr2-127702021-A-C

Variant names:

• chr2-127702021-A-C
• rs764196475
• NM_032740.4:c.493A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_032740.4(SFT2D3):​c.493A>C​(p.Ser165Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000175 in 1,145,992 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S165G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: SFT2D3 NM_032740.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.99
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFT2D3	NM_032740.4	c.493A>C	p.Ser165Arg	missense_variant	Exon 1 of 1	ENST00000310981.6	NP_116129.3
WDR33	NM_018383.5	c.*4302T>G		3_prime_UTR_variant	Exon 22 of 22	ENST00000322313.9	NP_060853.3
WDR33	XM_011511436.2	c.*4302T>G		3_prime_UTR_variant	Exon 22 of 22		XP_011509738.1
WDR33	XM_005263697.4	c.*4472T>G		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.493A>C	p.Ser165Arg	missense_variant	Exon 1 of 1	6	NM_032740.4	ENSP00000310803.3
WDR33	ENST00000322313.9	c.*4302T>G		3_prime_UTR_variant	Exon 22 of 22	1	NM_018383.5	ENSP00000325377.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000175 AC: 2 AN: 1145992 Hom.: 0 Cov.: 31 AF XY: 0.00000180 AC XY: 1 AN XY: 554934

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22464

American (AMR) AF: 0.00 AC: 0 AN: 8510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14668

East Asian (EAS) AF: 0.00 AC: 0 AN: 24710

South Asian (SAS) AF: 0.0000233 AC: 1 AN: 42912

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3066

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 957674

Other (OTH) AF: 0.0000220 AC: 1 AN: 45522

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.00209 AC: 7 AN: 3372

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.493A>C (p.S165R) alteration is located in exon 1 (coding exon 1) of the SFT2D3 gene. This alteration results from a A to C substitution at nucleotide position 493, causing the serine (S) at amino acid position 165 to be replaced by an arginine (R). 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	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		3.0
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.98	D
Vest4		0.73
MutPred		0.69		Loss of catalytic residue at S165 (P = 0.0205);
MVP		0.72
ClinPred		1.0	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.75
Mutation Taster		=18/82	disease causing

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

Other links and lift over

dbSNP: rs764196475; hg19: chr2-128459595;