rs539104890

Variant names:

• chr20-39001736-C-T
• rs539104890
• NM_021931.4:c.649C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-39001736-C-T
• chr20-39001736-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_021931.4(DHX35):​c.649C>T​(p.Arg217Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000287 in 1,603,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: DHX35 NM_021931.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.10
• Publications: 2 publications found

Genes affected

DHX35 (HGNC:15861): (DEAH-box helicase 35) 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 the DEAD box protein family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. The function of this gene product which is a member of this family, has not been determined. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jun 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021931.4. 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
	DHX35	NM_021931.4	MANE Select	c.649C>T	p.Arg217Trp	missense	Exon 9 of 22	NP_068750.2
	DHX35	NM_001190809.2		c.556C>T	p.Arg186Trp	missense	Exon 8 of 21	NP_001177738.1	Q9H5Z1-2
	DHX35	NR_033905.2		n.693C>T		non_coding_transcript_exon	Exon 9 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHX35	ENST00000252011.8	TSL:1 MANE Select	c.649C>T	p.Arg217Trp	missense	Exon 9 of 22	ENSP00000252011.3	Q9H5Z1-1
	DHX35	ENST00000954514.1		c.649C>T	p.Arg217Trp	missense	Exon 9 of 22	ENSP00000624573.1
	DHX35	ENST00000954516.1		c.643C>T	p.Arg215Trp	missense	Exon 9 of 22	ENSP00000624575.1

Frequencies

GnomAD3 genomes AF: 0.0000724 AC: 11 AN: 151944 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000286 AC: 7 AN: 245052 AF XY: 0.0000227

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000301

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.0000553

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000248 AC: 36 AN: 1451164 Hom.: 0 Cov.: 30 AF XY: 0.0000236 AC XY: 17 AN XY: 720988

African (AFR) AF: 0.0000606 AC: 2 AN: 33006

American (AMR) AF: 0.0000232 AC: 1 AN: 43188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25938

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39542

South Asian (SAS) AF: 0.0000481 AC: 4 AN: 83098

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53230

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5708

European-Non Finnish (NFE) AF: 0.0000181 AC: 20 AN: 1107410

Other (OTH) AF: 0.0000833 AC: 5 AN: 60044

GnomAD4 genome AF: 0.0000658 AC: 10 AN: 152062 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74318

African (AFR) AF: 0.00 AC: 0 AN: 41472

American (AMR) AF: 0.000131 AC: 2 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000109 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.1
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.13
Sift	Benign	0.18	T
Sift4G	Benign	0.18	T
Polyphen		0.97	D
Vest4		0.37
MVP		0.59
MPC		0.16
ClinPred		0.74	D
GERP RS		3.6
Varity_R		0.11
gMVP		0.61
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.39		Position offset: -6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs539104890; hg19: chr20-37630379; COSMIC: COSV52670221;