NM_003587.5:c.2347C>T

Variant names:

• chr6-30656474-G-A
• rs772762809
• NM_003587.5:c.2347C>T

Variant summary

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

The NM_003587.5(DHX16):​c.2347C>T​(p.Pro783Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P783A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DHX16 NM_003587.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.07
• Publications: 3 publications found

Genes affected

DHX16 (HGNC:2739): (DEAH-box helicase 16) 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. This gene encodes a DEAD box protein, which is a functional homolog of fission yeast Prp8 protein involved in cell cycle progression. This gene is mapped to the MHC region on chromosome 6p21.3, a region where many malignant, genetic and autoimmune disease genes are linked. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2018]

DHX16 Gene-Disease associations (from GenCC):

• neuromuscular disease and ocular or auditory anomalies with or without seizures

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

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_003587.5. 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
	DHX16	NM_003587.5	MANE Select	c.2347C>T	p.Pro783Ser	missense	Exon 15 of 20	NP_003578.2	O60231
	DHX16	NM_001164239.2		c.2167C>T	p.Pro723Ser	missense	Exon 15 of 20	NP_001157711.1	A0A1U9X7L7
	DHX16	NM_001363515.2		c.904C>T	p.Pro302Ser	missense	Exon 16 of 21	NP_001350444.1	Q5SQH5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHX16	ENST00000376442.8	TSL:1 MANE Select	c.2347C>T	p.Pro783Ser	missense	Exon 15 of 20	ENSP00000365625.3	O60231
	DHX16	ENST00000376437.9	TSL:1	c.904C>T	p.Pro302Ser	missense	Exon 7 of 12	ENSP00000365620.5	Q5SQH5
	DHX16	ENST00000934642.1		c.2368C>T	p.Pro790Ser	missense	Exon 15 of 20	ENSP00000604701.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251440 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	0.096
Eigen_PC	Benign	0.036
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Benign	0.24
Sift	Benign	0.031	D
Sift4G	Uncertain	0.050	T
Polyphen		1.0	D
Vest4		0.50
MutPred		0.50		Loss of catalytic residue at P783 (P = 8e-04)
MVP		0.45
MPC		0.60
ClinPred		0.97	D
GERP RS		3.3
Varity_R		0.15
gMVP		0.77
Mutation Taster		=27/73	disease causing

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

Other links and lift over

dbSNP: rs772762809; hg19: chr6-30624251;