Genetic Variant SFT2D3:p.Ser116Leu (chr2-127701875-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_032740.4(SFT2D3):c.347C>T(p.Ser116Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000459 in 1,306,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. S116W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000046 ( 0 hom. )

Consequence

SFT2D3
NM_032740.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.87

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.921

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFT2D3	NM_032740.4 link	c.347C>T	p.Ser116Leu	missense_variant	Exon 1 of 1	ENST00000310981.6	NP_116129.3	Q587I9
WDR33	NM_018383.5 link	c.*4448G>A		3_prime_UTR_variant	Exon 22 of 22	ENST00000322313.9	NP_060853.3	Q9C0J8-1
WDR33	XM_011511436.2 link	c.*4448G>A		3_prime_UTR_variant	Exon 22 of 22		XP_011509738.1	Q9C0J8-1
WDR33	XM_005263697.4 link	c.*4618G>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.347C>T	p.Ser116Leu	missense_variant	Exon 1 of 1	6	NM_032740.4	ENSP00000310803.3		Q587I9
WDR33	ENST00000322313.9 link	c.*4448G>A		3_prime_UTR_variant	Exon 22 of 22	1	NM_018383.5	ENSP00000325377.3		Q9C0J8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000459

AC:

AN:

1306096

Hom.:

Cov.:

AF XY:

0.00000776

AC XY:

AN XY:

644538

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26076

American (AMR)

AF:

0.00

AC:

AN:

24718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22520

East Asian (EAS)

AF:

0.00

AC:

AN:

27228

South Asian (SAS)

AF:

0.0000276

AC:

AN:

72520

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3960

European-Non Finnish (NFE)

AF:

0.00000384

AC:

AN:

1042782

Other (OTH)

AF:

0.00

AC:

AN:

53718

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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

Pathogenic

0.67

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Benign

0.61

LIST_S2

Uncertain

0.87

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

-0.28

MutationAssessor

Pathogenic

3.2

PhyloP100

3.9

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.41

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.67

MutPred

0.67

Loss of MoRF binding (P = 0.0921);

MVP

0.80

ClinPred

1.0

GERP RS

3.5

PromoterAI

-0.061

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.92

gMVP

0.77

Mutation Taster

=16/84

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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chr2-127701875-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