14-60152941-G-A

Position:

• chr14-60152941-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016029.4(DHRS7):​c.631C>T​(p.Arg211Trp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,990 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R211Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: DHRS7 NM_016029.4 missense, splice_region
• Scores: Splicing: ADA: 0.9981
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.78

Genes affected

DHRS7 (HGNC:21524): (dehydrogenase/reductase 7) This gene encodes a member of the short-chain dehydrogenases/reductases (SDR) family, which has over 46,000 members. Members in this family are enzymes that metabolize many different compounds, such as steroid hormones, prostaglandins, retinoids, lipids and xenobiotics. [provided by RefSeq, Apr 2016]

PCNX4 (HGNC:20349): (pecanex 4) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHRS7	NM_016029.4	c.631C>T	p.Arg211Trp	missense_variant, splice_region_variant	4/7	ENST00000557185.6
DHRS7	NM_001322280.2	c.481C>T	p.Arg161Trp	missense_variant, splice_region_variant	4/7
DHRS7	NM_001322281.2	c.211C>T	p.Arg71Trp	missense_variant, splice_region_variant	4/7
DHRS7	NM_001322282.2	c.393+1018C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHRS7	ENST00000557185.6	c.631C>T	p.Arg211Trp	missense_variant, splice_region_variant	4/7	1	NM_016029.4	P1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.0000759 AC: 19 AN: 250414 Hom.: 0 AF XY: 0.0000665 AC XY: 9 AN XY: 135424

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461724 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727166

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74462

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000946

Bravo AF: 0.000389

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

The c.631C>T (p.R211W) alteration is located in exon 4 (coding exon 4) of the DHRS7 gene. This alteration results from a C to T substitution at nucleotide position 631, causing the arginine (R) at amino acid position 211 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;D;T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;.;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	1.8	L;L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.8	D;D;.;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0040	D;D;.;D
Sift4G	Uncertain	0.019	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.52
MutPred		0.61		Loss of methylation at R211 (P = 0.0126);Loss of methylation at R211 (P = 0.0126);Loss of methylation at R211 (P = 0.0126);.;
MVP		1.0
MPC		0.27
ClinPred		0.66	D
GERP RS		5.4
Varity_R		0.28
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.83
SpliceAI score (max)		0.12		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: rs751714239; hg19: chr14-60619659; COSMIC: COSV53665195; COSMIC: COSV53665195;