16-72112469-G-C

Position:

• chr16-72112469-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000268482.8(DHX38):​c.3656G>C​(p.Arg1219Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1219C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DHX38 ENST00000268482.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.70

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]

PMFBP1 (HGNC:17728): (polyamine modulated factor 1 binding protein 1) Involved in spermatogenesis. Located in sperm connecting piece. Implicated in spermatogenic failure 31. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHX38	NM_014003.4	c.3656G>C	p.Arg1219Pro	missense_variant	27/27	ENST00000268482.8	NP_054722.2
DHX38	XM_011523484.3	c.3656G>C	p.Arg1219Pro	missense_variant	27/28		XP_011521786.1
DHX38	XM_047434985.1	c.3656G>C	p.Arg1219Pro	missense_variant	27/28		XP_047290941.1
DHX38	XM_017023913.3	c.3551G>C	p.Arg1184Pro	missense_variant	26/27		XP_016879402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHX38	ENST00000268482.8	c.3656G>C	p.Arg1219Pro	missense_variant	27/27	1	NM_014003.4	ENSP00000268482	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 28, 2023

The c.3656G>C (p.R1219P) alteration is located in exon 27 (coding exon 26) of the DHX38 gene. This alteration results from a G to C substitution at nucleotide position 3656, causing the arginine (R) at amino acid position 1219 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.0095	T
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.8	D;.
REVEL	Benign	0.14
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.011	D;D
Polyphen		0.99	D;.
Vest4		0.60
MutPred		0.26		Loss of MoRF binding (P = 0.001);.;
MVP		0.63
MPC		1.8
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.63
gMVP		0.52

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-72146368; COSMIC: COSV51700682; COSMIC: COSV51700682;