rs766053952

Variant names:

• chr16-72099742-G-A
• rs766053952
• NM_014003.4:c.971G>A
• DHX38 p.Arg324Gln

Your query was ambiguous. Multiple possible variants found:

• chr16-72099742-G-A
• chr16-72099742-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_014003.4(DHX38):​c.971G>A​(p.Arg324Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R324G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DHX38 NM_014003.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 9.41
• Publications: 4 publications found

Genes affected

DHX38 (HGNC:17211): (DEAH-box helicase 38) 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. The protein encoded by this gene is a member of the DEAD/H box family of splicing factors. This protein resembles yeast Prp16 more closely than other DEAD/H family members. It is an ATPase and essential for the catalytic step II in pre-mRNA splicing process. [provided by RefSeq, Jul 2008]

DHX38 Gene-Disease associations (from GenCC):

• retinitis pigmentosa 84

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD, AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84
• PP5: Variant 16-72099742-G-A is Pathogenic according to our data. Variant chr16-72099742-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 592160.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014003.4. 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
	DHX38	NM_014003.4	MANE Select	c.971G>A	p.Arg324Gln	missense	Exon 8 of 27	NP_054722.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHX38	ENST00000268482.8	TSL:1 MANE Select	c.971G>A	p.Arg324Gln	missense	Exon 8 of 27	ENSP00000268482.3	Q92620-1
	DHX38	ENST00000904787.1		c.971G>A	p.Arg324Gln	missense	Exon 8 of 27	ENSP00000574846.1
	DHX38	ENST00000904788.1		c.971G>A	p.Arg324Gln	missense	Exon 8 of 27	ENSP00000574847.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251202 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461790 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727182

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.0000224 AC: 1 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000251 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Retinitis pigmentosa 84 (2)
1	-	-	Autosomal recessive retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	0.00054	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		9.4
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.020	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.88
Mutation Taster		=27/73	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs766053952;

hg19: chr16-72133641;