chr12-124968903-G-T

Position:

• chr12-124968903-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:4
• Conservation: PhyloP100: 5.29

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 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 id is 402139.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-124968903-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHX37	NM_032656.4	c.1257C>A	p.Asn419Lys	missense_variant	9/27	ENST00000308736.7	NP_116045.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHX37	ENST00000308736.7	c.1257C>A	p.Asn419Lys	missense_variant	9/27	1	NM_032656.4	ENSP00000311135	P1
DHX37	ENST00000544745.2	c.729C>A	p.Asn243Lys	missense_variant	6/23	1		ENSP00000439009
DHX37	ENST00000679875.1	n.1329C>A		non_coding_transcript_exon_variant	9/18

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability;C4022738:Neurodevelopmental delay Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

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

May 30, 2019

- -

Abnormal brain morphology Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

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

-

There is one more families with similar phenotype -

Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 20, 2020

- -

Neurodevelopmental disorders Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;.
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.7	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
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	D
GERP RS		2.7
Varity_R		0.41
gMVP		0.86

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: rs1060499737; hg19: chr12-125453449;