2-127701785-T-A

Position:

• chr2-127701785-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032740.4(SFT2D3):​c.257T>A​(p.Leu86Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000459 in 1,445,710 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (1 hom.)
• Consequence: SFT2D3 NM_032740.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.75

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013540357).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SFT2D3	NM_032740.4	c.257T>A	p.Leu86Gln	missense_variant	1/1	ENST00000310981.6	NP_116129.3
WDR33	NM_018383.5	c.*4538A>T		3_prime_UTR_variant	22/22	ENST00000322313.9	NP_060853.3
WDR33	XM_011511436.2	c.*4538A>T		3_prime_UTR_variant	22/22		XP_011509738.1
WDR33	XM_005263697.4	c.*4708A>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	c.257T>A	p.Leu86Gln	missense_variant	1/1	6	NM_032740.4	ENSP00000310803.3
WDR33	ENST00000322313	c.*4538A>T		3_prime_UTR_variant	22/22	1	NM_018383.5	ENSP00000325377.3

Frequencies

GnomAD3 genomes AF: 0.000465 AC: 70 AN: 150536 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00112

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: 0.000728

Gnomad OTH AF: 0.000484

GnomAD3 exomes AF: 0.000523 AC: 39 AN: 74570 Hom.: 0 AF XY: 0.000441 AC XY: 19 AN XY: 43052

Gnomad AFR exome AF: 0.00114

Gnomad AMR exome AF: 0.00105

Gnomad ASJ exome AF: 0.000152

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000697

Gnomad OTH exome AF: 0.00140

GnomAD4 exome AF: 0.000459 AC: 594 AN: 1295066 Hom.: 1 Cov.: 31 AF XY: 0.000441 AC XY: 282 AN XY: 639022

Gnomad4 AFR exome AF: 0.0000382

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.0000448

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000521

Gnomad4 OTH exome AF: 0.000415

GnomAD4 genome AF: 0.000465 AC: 70 AN: 150644 Hom.: 0 Cov.: 33 AF XY: 0.000530 AC XY: 39 AN XY: 73550

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00112

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000728

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000582 Hom.: 0

Bravo AF: 0.000491

ExAC AF: 0.000171 AC: 5

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

Apr 15, 2024

The c.257T>A (p.L86Q) alteration is located in exon 1 (coding exon 1) of the SFT2D3 gene. This alteration results from a T to A substitution at nucleotide position 257, causing the leucine (L) at amino acid position 86 to be replaced by a glutamine (Q). 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	0.62
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.23
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.059	T
Polyphen		1.0	D
Vest4		0.55
MVP		0.73
ClinPred		0.054	T
GERP RS		3.8
Varity_R		0.60
gMVP		0.51

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: rs763854556; hg19: chr2-128459359;