3-52394609-G-C

Position:

• chr3-52394609-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000420323.7(DNAH1):​c.10771G>C​(p.Val3591Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000759 in 1,449,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: DNAH1 ENST00000420323.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.200

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07148984).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.10771G>C	p.Val3591Leu	missense_variant	67/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.10840G>C	p.Val3614Leu	missense_variant	69/80		XP_016861618.1
DNAH1	XM_017006130.2	c.10771G>C	p.Val3591Leu	missense_variant	68/79		XP_016861619.1
DNAH1	XM_017006131.2	c.10714G>C	p.Val3572Leu	missense_variant	68/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.10771G>C	p.Val3591Leu	missense_variant	67/78	1	NM_015512.5	ENSP00000401514	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000376 AC: 9 AN: 239398 Hom.: 0 AF XY: 0.0000155 AC XY: 2 AN XY: 129370

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000267

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000759 AC: 11 AN: 1449692 Hom.: 0 Cov.: 32 AF XY: 0.00000417 AC XY: 3 AN XY: 719656

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000250

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000264

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2021

This sequence change replaces valine with leucine at codon 3591 of the DNAH1 protein (p.Val3591Leu). The valine residue is moderately conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs755963386, ExAC 0.03%). This variant has not been reported in the literature in individuals affected with DNAH1-related conditions. 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. 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. -

DNAH1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 25, 2024

The DNAH1 c.10771G>C variant is predicted to result in the amino acid substitution p.Val3591Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.027% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	3.3
DANN	Benign	0.92
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.046
Sift	Benign	0.30	T
Sift4G	Benign	0.33	T
Vest4		0.34
MutPred		0.44		Gain of ubiquitination at K3592 (P = 0.1204);
MVP		0.095
MPC		0.13
ClinPred		0.021	T
GERP RS		-1.7
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs755963386; hg19: chr3-52428625;