12-124947836-A-G

Position:

• chr12-124947836-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032656.4(DHX37):​c.3440T>C​(p.Ile1147Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00219 in 1,603,458 control chromosomes in the GnomAD database, including 13 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0022 (12 hom.)
• Consequence: DHX37 NM_032656.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.63

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005722761).
• BP6: Variant 12-124947836-A-G is Benign according to our data. Variant chr12-124947836-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 735695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00206 (314/152264) while in subpopulation NFE AF= 0.0036 (245/68014). AF 95% confidence interval is 0.00323. There are 1 homozygotes in gnomad4. There are 132 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHX37	NM_032656.4	c.3440T>C	p.Ile1147Thr	missense_variant	27/27	ENST00000308736.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHX37	ENST00000308736.7	c.3440T>C	p.Ile1147Thr	missense_variant	27/27	1	NM_032656.4	P1
DHX37	ENST00000544745.2	c.*108T>C		3_prime_UTR_variant	23/23	1
DHX37	ENST00000507267.2	n.584T>C		non_coding_transcript_exon_variant	2/2	1
DHX37	ENST00000542400.5	n.2054T>C		non_coding_transcript_exon_variant	6/6	2

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 314 AN: 152146 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00360

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00188 AC: 451 AN: 240518 Hom.: 1 AF XY: 0.00182 AC XY: 236 AN XY: 129598

Gnomad AFR exome AF: 0.000435

Gnomad AMR exome AF: 0.000208

Gnomad ASJ exome AF: 0.00280

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00263

Gnomad NFE exome AF: 0.00318

Gnomad OTH exome AF: 0.00241

GnomAD4 exome AF: 0.00221 AC: 3200 AN: 1451194 Hom.: 12 Cov.: 30 AF XY: 0.00218 AC XY: 1571 AN XY: 720784

Gnomad4 AFR exome AF: 0.000210

Gnomad4 AMR exome AF: 0.000228

Gnomad4 ASJ exome AF: 0.00155

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00306

Gnomad4 NFE exome AF: 0.00259

Gnomad4 OTH exome AF: 0.00200

GnomAD4 genome AF: 0.00206 AC: 314 AN: 152264 Hom.: 1 Cov.: 34 AF XY: 0.00177 AC XY: 132 AN XY: 74434

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00339

Gnomad4 NFE AF: 0.00360

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00292 Hom.: 3

Bravo AF: 0.00181

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00194 AC: 236

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	DHX37: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	- -

DHX37-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.19
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.30	B
Vest4		0.24
MVP		0.18
MPC		0.34
ClinPred		0.040	T
GERP RS		5.1
Varity_R		0.16
gMVP		0.50

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: rs148973591; hg19: chr12-125432382;