rs4606565

Variant names:

• chr12-124954003-A-G
• rs4606565
• NM_032656.4:c.2579-7T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-124954003-A-G
• chr12-124954003-A-C
• chr12-124954003-A-T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 13 publications found

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: G2P, Labcorp Genetics (formerly Invitae), 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

ENSG00000301157 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032656.4. 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
	DHX37	NM_032656.4	MANE Select	c.2579-7T>C		splice_region intron	N/A	NP_116045.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHX37	ENST00000308736.7	TSL:1 MANE Select	c.2579-7T>C		splice_region intron	N/A	ENSP00000311135.2	Q8IY37
	DHX37	ENST00000544745.2	TSL:1	c.2048-7T>C		splice_region intron	N/A	ENSP00000439009.2	F5H3Y4
	DHX37	ENST00000880032.1		c.2486-7T>C		splice_region intron	N/A	ENSP00000550091.1

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

GnomAD2 exomes AF: 0.646 AC: 161356 AN: 249944 AF XY: 0.648

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 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

African (AFR) AF: 0.446 AC: 14915 AN: 33472

American (AMR) AF: 0.698 AC: 31214 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.678 AC: 17715 AN: 26126

East Asian (EAS) AF: 0.831 AC: 32982 AN: 39692

South Asian (SAS) AF: 0.756 AC: 65219 AN: 86256

European-Finnish (FIN) AF: 0.651 AC: 34464 AN: 52950

Middle Eastern (MID) AF: 0.659 AC: 3802 AN: 5768

European-Non Finnish (NFE) AF: 0.584 AC: 649310 AN: 1111886

Other (OTH) AF: 0.621 AC: 37498 AN: 60374

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

African (AFR) AF: 0.449 AC: 18607 AN: 41450

American (AMR) AF: 0.647 AC: 9884 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 2386 AN: 3470

East Asian (EAS) AF: 0.839 AC: 4320 AN: 5148

South Asian (SAS) AF: 0.775 AC: 3735 AN: 4822

European-Finnish (FIN) AF: 0.667 AC: 7055 AN: 10570

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.592 AC: 40198 AN: 67936

Other (OTH) AF: 0.596 AC: 1258 AN: 2112

Alfa AF: 0.582 Hom.: 11422

Bravo AF: 0.570

Asia WGS AF: 0.802 AC: 2788 AN: 3478

EpiCase AF: 0.591

EpiControl AF: 0.589

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	46,XY sex reversal 11 (1)
-	-	1	Neurodevelopmental disorder with brain anomalies and with or without vertebral or cardiac anomalies (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.6
DANN	Benign	0.37
PhyloP100		-0.16
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		2.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4606565; hg19: chr12-125438549;