Genetic Variant SDR16C5:p.Val251Phe (chr8-56305682-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_138969.4(SDR16C5):c.751G>T(p.Val251Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000828 in 1,449,432 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

SDR16C5
NM_138969.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.93

Variant links:

Genes affected

SDR16C5 (HGNC:30311): (short chain dehydrogenase/reductase family 16C member 5) This gene encodes a member of the short-chain alcohol dehydrogenase/reductase superfamily of proteins and is involved in the oxidation of retinol to retinaldehyde. The encoded protein is associated with the endoplasmic reticulum and is predicted to contain three transmembrane helices, suggesting that it is an integral membrane protein. It recognizes all-trans-retinol and all-trans-retinaldehyde as substrates and exhibits a strong preference for NAD(+)/NADH as cofactors. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

SDR16C5 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDR16C5	NM_138969.4 link	c.751G>T	p.Val251Phe	missense_variant	Exon 6 of 7	ENST00000303749.8	NP_620419.2	Q8N3Y7-1B3KT84
SDR16C5	NM_001318049.2 link	c.751G>T	p.Val251Phe	missense_variant	Exon 6 of 8		NP_001304978.1	Q8N3Y7G3V145B3KT84
SDR16C5	NM_001318050.2 link	c.619G>T	p.Val207Phe	missense_variant	Exon 5 of 6		NP_001304979.1	Q8N3Y7-2B3KT84

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SDR16C5	ENST00000303749.8 link	c.751G>T	p.Val251Phe	missense_variant	Exon 6 of 7	1	NM_138969.4	ENSP00000307607.3	Q8N3Y7-1
SDR16C5	ENST00000396721.6 link	c.619G>T	p.Val207Phe	missense_variant	Exon 5 of 6	1		ENSP00000379947.2	Q8N3Y7-2
SDR16C5	ENST00000522671.1 link	c.751G>T	p.Val251Phe	missense_variant	Exon 6 of 8	2		ENSP00000431010.1	G3V145

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000249

AC:

AN:

240702

Hom.:

AF XY:

0.0000231

AC XY:

AN XY:

130130

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000127

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000903

Gnomad OTH exome

AF:

0.000172

GnomAD4 exome

AF:

0.00000828

AC:

AN:

1449432

Hom.:

Cov.:

AF XY:

0.00000972

AC XY:

AN XY:

720338

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000166

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000361

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.751G>T (p.V251F) alteration is located in exon 6 (coding exon 5) of the SDR16C5 gene. This alteration results from a G to T substitution at nucleotide position 751, causing the valine (V) at amino acid position 251 to be replaced by a phenylalanine (F). 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

0.82

BayesDel_addAF

Benign

-0.038

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

.;T;T

Eigen

Benign

0.16

Eigen_PC

Benign

0.039

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.84

T;D;D

M_CAP

Benign

0.073

MetaRNN

Pathogenic

0.87

D;D;D

MetaSVM

Uncertain

0.34

MutationAssessor

Pathogenic

3.3

.;M;.

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-2.7

D;D;D

REVEL

Uncertain

0.49

Sift

Uncertain

0.0050

D;D;D

Sift4G

Uncertain

0.017

D;D;D

Polyphen

0.82

P;B;P

Vest4

0.66

MutPred

0.70

.;Gain of ubiquitination at K248 (P = 0.1283);Gain of ubiquitination at K248 (P = 0.1283);

MVP

0.88

MPC

0.23

ClinPred

0.52

GERP RS

5.6

Varity_R

0.30

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over