14-60150172-G-C

Variant names:

• chr14-60150172-G-C
• rs1427986469
• NM_016029.4:c.649C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_016029.4(DHRS7):​c.649C>G​(p.Leu217Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000074 in 1,351,208 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. L217F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: DHRS7 NM_016029.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.30
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016029.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHRS7	NM_016029.4	MANE Select	c.649C>G	p.Leu217Val	missense	Exon 5 of 7	NP_057113.1	Q9Y394-1
	DHRS7	NM_001322280.2		c.499C>G	p.Leu167Val	missense	Exon 5 of 7	NP_001309209.1	Q9Y394-2
	DHRS7	NM_001322282.2		c.409C>G	p.Leu137Val	missense	Exon 4 of 6	NP_001309211.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHRS7	ENST00000557185.6	TSL:1 MANE Select	c.649C>G	p.Leu217Val	missense	Exon 5 of 7	ENSP00000451882.1	Q9Y394-1
	DHRS7	ENST00000536410.6	TSL:1	c.499C>G	p.Leu167Val	missense	Exon 5 of 7	ENSP00000442993.2	Q9Y394-2
	DHRS7	ENST00000554101.5	TSL:2	c.631C>G	p.Leu211Val	missense	Exon 5 of 6	ENSP00000450899.1	H0YJ66

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.40e-7 AC: 1 AN: 1351208 Hom.: 0 Cov.: 32 AF XY: 0.00000150 AC XY: 1 AN XY: 668482

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27894

American (AMR) AF: 0.00 AC: 0 AN: 30340

Ashkenazi Jewish (ASJ) AF: 0.0000447 AC: 1 AN: 22394

East Asian (EAS) AF: 0.00 AC: 0 AN: 35348

South Asian (SAS) AF: 0.00 AC: 0 AN: 63740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5306

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1060954

Other (OTH) AF: 0.00 AC: 0 AN: 55066

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.3
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.57
Sift	Benign	0.068	T
Sift4G	Uncertain	0.049	D
Polyphen		1.0	D
Vest4		0.59
MutPred		0.82		Loss of stability (P = 0.084)
MVP		1.0
MPC		0.22
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.34
gMVP		0.82
Mutation Taster		=17/83	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1427986469; hg19: chr14-60616890;