14-60150179-A-T

Position:

• chr14-60150179-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016029.4(DHRS7):​c.642T>A​(p.Phe214Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: DHRS7 NM_016029.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.289

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33736074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHRS7	NM_016029.4	c.642T>A	p.Phe214Leu	missense_variant	5/7	ENST00000557185.6	NP_057113.1
DHRS7	NM_001322280.2	c.492T>A	p.Phe164Leu	missense_variant	5/7		NP_001309209.1
DHRS7	NM_001322282.2	c.402T>A	p.Phe134Leu	missense_variant	4/6		NP_001309211.1
DHRS7	NM_001322281.2	c.222T>A	p.Phe74Leu	missense_variant	5/7		NP_001309210.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHRS7	ENST00000557185.6	c.642T>A	p.Phe214Leu	missense_variant	5/7	1	NM_016029.4	ENSP00000451882	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2023

The c.642T>A (p.F214L) alteration is located in exon 5 (coding exon 5) of the DHRS7 gene. This alteration results from a T to A substitution at nucleotide position 642, causing the phenylalanine (F) at amino acid position 214 to be replaced by a leucine (L). 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	0.79
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	8.3
DANN	Benign	0.88
DEOGEN2	Uncertain	0.50	D;D;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.78	.;T;.;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.34	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	L;L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.9	D;D;.;D
REVEL	Uncertain	0.40
Sift	Benign	0.056	T;T;.;T
Sift4G	Benign	0.072	T;T;T;T
Polyphen		0.12	B;B;.;.
Vest4		0.39
MutPred		0.64		Loss of methylation at R211 (P = 0.1363);Loss of methylation at R211 (P = 0.1363);Loss of methylation at R211 (P = 0.1363);.;
MVP		0.88
MPC		0.071
ClinPred		0.29	T
GERP RS		-6.8
Varity_R		0.20
gMVP		0.75

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

LitVar

Other links and lift over

dbSNP: rs1327951158; hg19: chr14-60616897;