Genetic Variant NM_032656.4:c.1257C>A (chr12-124968903-G-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_032656.4(DHX37):c.1257C>A(p.Asn419Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Consequence

DHX37
NM_032656.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:4

Conservation

PhyloP100: 5.29

Publications

3 publications found

Variant links:

Genes affected

DHX37 (HGNC:17210): (DEAH-box helicase 37) This gene encodes a DEAD box protein. DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. [provided by RefSeq, Jul 2008]

DHX37 Gene-Disease associations (from GenCC):

46,XY sex reversal 11
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
46,XY complete gonadal dysgenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
46,XY partial gonadal dysgenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
testicular regression syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

DHX37 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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, 0.916

PP5

Variant 12-124968903-G-T is Pathogenic according to our data. Variant chr12-124968903-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 402139.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHX37	NM_032656.4 link	c.1257C>A	p.Asn419Lys	missense_variant	Exon 9 of 27	ENST00000308736.7	NP_116045.2	Q8IY37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DHX37	ENST00000308736.7 link	c.1257C>A	p.Asn419Lys	missense_variant	Exon 9 of 27	1	NM_032656.4	ENSP00000311135.2	Q8IY37
DHX37	ENST00000544745.2 link	c.726C>A	p.Asn242Lys	missense_variant	Exon 6 of 23	1		ENSP00000439009.2	F5H3Y4
DHX37	ENST00000679875.1 link	n.1329C>A		non_coding_transcript_exon_variant	Exon 9 of 18

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Intellectual disability;C4022738:Neurodevelopmental delay

Pathogenic:1

May 30, 2019

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Abnormal brain morphology

Pathogenic:1

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

There is one more families with similar phenotype -

Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies

Pathogenic:1

Apr 20, 2020

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Neurodevelopmental disorders

Pathogenic:1

University of Washington Center for Mendelian Genomics, University of Washington

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;T

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

D;.

M_CAP

Benign

0.030

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.7

H;.

PhyloP100

5.3

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-5.7

D;D

REVEL

Benign

0.20

Sift

Benign

0.054

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.87

P;.

Vest4

0.94

MutPred

0.70

Gain of methylation at N419 (P = 0.0329);.;

MVP

0.60

MPC

1.3

ClinPred

0.98

GERP RS

2.7

Varity_R

0.41

gMVP

0.86

Mutation Taster

=57/43

disease causing (ClinVar)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over