Genetic Variant SFT2D3:p.Arg127Trp (chr2-127701907-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032740.4(SFT2D3):c.379C>T(p.Arg127Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000154 in 1,298,588 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R127G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

SFT2D3
NM_032740.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.979

Publications

0 publications found

Variant links:

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]

SFT2D3 links:

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]

WDR33 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFT2D3	NM_032740.4 link	c.379C>T	p.Arg127Trp	missense_variant	Exon 1 of 1	ENST00000310981.6	NP_116129.3	Q587I9
WDR33	NM_018383.5 link	c.*4416G>A		3_prime_UTR_variant	Exon 22 of 22	ENST00000322313.9	NP_060853.3	Q9C0J8-1
WDR33	XM_011511436.2 link	c.*4416G>A		3_prime_UTR_variant	Exon 22 of 22		XP_011509738.1	Q9C0J8-1
WDR33	XM_005263697.4 link	c.*4586G>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 link	c.379C>T	p.Arg127Trp	missense_variant	Exon 1 of 1	6	NM_032740.4	ENSP00000310803.3		Q587I9
WDR33	ENST00000322313.9 link	c.*4416G>A		3_prime_UTR_variant	Exon 22 of 22	1	NM_018383.5	ENSP00000325377.3		Q9C0J8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000154

AC:

AN:

1298588

Hom.:

Cov.:

AF XY:

0.00000156

AC XY:

AN XY:

640454

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25724

American (AMR)

AF:

0.00

AC:

AN:

23018

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21910

East Asian (EAS)

AF:

0.00

AC:

AN:

27158

South Asian (SAS)

AF:

0.0000281

AC:

AN:

71202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3852

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1039998

Other (OTH)

AF:

0.00

AC:

AN:

53334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.0048

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.00063

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.71

M_CAP

Pathogenic

0.47

MetaRNN

Uncertain

0.50

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.2

PhyloP100

0.98

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.010

REVEL

Uncertain

0.32

Sift

Benign

0.23

Sift4G

Benign

0.14

Polyphen

1.0

Vest4

0.34

MutPred

0.64

Loss of methylation at R127 (P = 3e-04);

MVP

0.75

ClinPred

0.75

GERP RS

0.22

PromoterAI

0.0088

Neutral

(source)

Varity_R

0.13

gMVP

0.70

Mutation Taster

=37/63

disease causing

(source)

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

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2-127701907-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over