12-124954003-A-G

Position:

• chr12-124954003-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032656.4(DHX37):​c.2579-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.604 in 1,613,218 control chromosomes in the GnomAD database, including 299,320 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26328 hom., cov: 31)
  • Exomes 𝑓: 0.61 (272992 hom.)
• Consequence: DHX37 NM_032656.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003567
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.164

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 (BayesDel_noAF=-0.84).
• BP6: Variant 12-124954003-A-G is Benign according to our data. Variant chr12-124954003-A-G is described in ClinVar as [Benign]. Clinvar id is 1255490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.818 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHX37	NM_032656.4	c.2579-7T>C		splice_region_variant, intron_variant		ENST00000308736.7	NP_116045.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHX37	ENST00000308736.7	c.2579-7T>C		splice_region_variant, intron_variant		1	NM_032656.4	ENSP00000311135.2
DHX37	ENST00000544745.2	c.2048-7T>C		splice_region_variant, intron_variant		1		ENSP00000439009.2

Frequencies

GnomAD3 genomes AF: 0.579 AC: 88000 AN: 151868 Hom.: 26317 Cov.: 31

Gnomad AFR AF: 0.449

Gnomad AMI AF: 0.442

Gnomad AMR AF: 0.647

Gnomad ASJ AF: 0.688

Gnomad EAS AF: 0.839

Gnomad SAS AF: 0.775

Gnomad FIN AF: 0.667

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.592

Gnomad OTH AF: 0.594

GnomAD3 exomes AF: 0.646 AC: 161356 AN: 249944 Hom.: 53446 AF XY: 0.648 AC XY: 87790 AN XY: 135422

Gnomad AFR exome AF: 0.449

Gnomad AMR exome AF: 0.703

Gnomad ASJ exome AF: 0.677

Gnomad EAS exome AF: 0.843

Gnomad SAS exome AF: 0.765

Gnomad FIN exome AF: 0.660

Gnomad NFE exome AF: 0.586

Gnomad OTH exome AF: 0.639

GnomAD4 exome AF: 0.607 AC: 887119 AN: 1461232 Hom.: 272992 Cov.: 83 AF XY: 0.612 AC XY: 444642 AN XY: 726908

Gnomad4 AFR exome AF: 0.446

Gnomad4 AMR exome AF: 0.698

Gnomad4 ASJ exome AF: 0.678

Gnomad4 EAS exome AF: 0.831

Gnomad4 SAS exome AF: 0.756

Gnomad4 FIN exome AF: 0.651

Gnomad4 NFE exome AF: 0.584

Gnomad4 OTH exome AF: 0.621

GnomAD4 genome AF: 0.579 AC: 88041 AN: 151986 Hom.: 26328 Cov.: 31 AF XY: 0.586 AC XY: 43558 AN XY: 74288

Gnomad4 AFR AF: 0.449

Gnomad4 AMR AF: 0.647

Gnomad4 ASJ AF: 0.688

Gnomad4 EAS AF: 0.839

Gnomad4 SAS AF: 0.775

Gnomad4 FIN AF: 0.667

Gnomad4 NFE AF: 0.592

Gnomad4 OTH AF: 0.596

Alfa AF: 0.583 Hom.: 11328

Bravo AF: 0.570

Asia WGS AF: 0.802 AC: 2788 AN: 3478

EpiCase AF: 0.591

EpiControl AF: 0.589

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

46,XY sex reversal 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.6
DANN	Benign	0.37
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		2.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000036
dbscSNV1_RF	Benign	0.0
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: rs4606565; hg19: chr12-125438549;