rs767190386

Variant names:

• chr3-52383557-C-G
• NM_015512.5:c.8113C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-52383557-C-G
• chr3-52383557-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015512.5(DNAH1):​c.8113C>G​(p.Arg2705Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.934

Genes affected

DNAH1 (HGNC:2940): (dynein axonemal heavy chain 1) This gene encodes an inner dynein arm heavy chain that provides structural support between the radial spokes and the outer doublet of the sperm tail. Naturally occurring mutations in this gene are associated with primary ciliary dyskinesia and multiple morphological anomalies of the flagella that result in asthenozoospermia and male infertility. Mice with a homozygous knockout of the orthologous gene are viable but have reduced sperm motility and are infertile. [provided by RefSeq, Feb 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.801

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.8113C>G	p.Arg2705Gly	missense_variant	Exon 51 of 78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.8182C>G	p.Arg2728Gly	missense_variant	Exon 53 of 80		XP_016861618.1
DNAH1	XM_017006130.2	c.8113C>G	p.Arg2705Gly	missense_variant	Exon 52 of 79		XP_016861619.1
DNAH1	XM_017006131.2	c.8182C>G	p.Arg2728Gly	missense_variant	Exon 53 of 79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.8113C>G	p.Arg2705Gly	missense_variant	Exon 51 of 78	1	NM_015512.5	ENSP00000401514.2
DNAH1	ENST00000486752.5	n.8374C>G		non_coding_transcript_exon_variant	Exon 51 of 77	2

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

Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 Uncertain:1

May 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with DNAH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 2705 of the DNAH1 protein (p.Arg2705Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.45	T
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Benign	0.25
Sift	Uncertain	0.019	D
Sift4G	Benign	0.066	T
Vest4		0.80
MutPred		0.65		Loss of MoRF binding (P = 0.018);
MVP		0.48
MPC		0.26
ClinPred		0.96	D
GERP RS		3.7
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr3-52417573;