2-127701785-T-A

Variant names:

• chr2-127701785-T-A
• rs763854556
• NM_032740.4:c.257T>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. 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
• Publications: 1 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013540357).

Transcripts

RefSeq

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

GnomAD2 exomes AF: 0.000523 AC: 39 AN: 74570 AF XY: 0.000441

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 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

African (AFR) AF: 0.0000382 AC: 1 AN: 26160

American (AMR) AF: 0.00114 AC: 28 AN: 24634

Ashkenazi Jewish (ASJ) AF: 0.0000448 AC: 1 AN: 22342

East Asian (EAS) AF: 0.00 AC: 0 AN: 26862

South Asian (SAS) AF: 0.00 AC: 0 AN: 71440

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32300

Middle Eastern (MID) AF: 0.000775 AC: 3 AN: 3870

European-Non Finnish (NFE) AF: 0.000521 AC: 539 AN: 1034450

Other (OTH) AF: 0.000415 AC: 22 AN: 53008

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

African (AFR) AF: 0.0000724 AC: 3 AN: 41422

American (AMR) AF: 0.00112 AC: 17 AN: 15162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3440

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000728 AC: 49 AN: 67272

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

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

Apr 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		2.7
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
PromoterAI		-0.052	Neutral
Varity_R		0.60
gMVP		0.51
Mutation Taster		=50/50

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: rs763854556; hg19: chr2-128459359;