rs140883175

chr3-52357632-G-Achr3-52357632-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_015512.5(DNAH1):c.3877G>A(p.Asp1293Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000206 in 1,600,730 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00037 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 4.91

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21810189).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.3877G>A	p.Asp1293Asn	missense_variant	23/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.3877G>A	p.Asp1293Asn	missense_variant	24/80
DNAH1	XM_017006130.2	c.3877G>A	p.Asp1293Asn	missense_variant	24/79
DNAH1	XM_017006131.2	c.3877G>A	p.Asp1293Asn	missense_variant	24/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.3877G>A	p.Asp1293Asn	missense_variant	23/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.4138G>A		non_coding_transcript_exon_variant	23/77	2

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152096 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000206 AC: 47 AN: 228418 Hom.: 0 AF XY: 0.000226 AC XY: 28 AN XY: 123706

Gnomad AFR exome AF: 0.000148

Gnomad AMR exome AF: 0.000461

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000590

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000216

Gnomad OTH exome AF: 0.00123

GnomAD4 exome AF: 0.000189 AC: 274 AN: 1448516 Hom.: 1 Cov.: 31 AF XY: 0.000202 AC XY: 145 AN XY: 719300

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000742

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000188

Gnomad4 OTH exome AF: 0.000384

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152214 Hom.: 1 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74416

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.000157 Hom.: 0

Bravo AF: 0.000756

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000244 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000149 AC: 18

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spermatogenic failure 18 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 20, 2017

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1293 of the DNAH1 protein (p.Asp1293Asn). This variant is present in population databases (rs140883175, gnomAD 0.05%). This missense change has been observed in individual(s) with multiple morph abnormalities of the sperm flagella (PMID: 24360805). ClinVar contains an entry for this variant (Variation ID: 430856). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DNAH1 protein function with a negative predictive value of 80%. 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, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 07, 2022

The DNAH1 c.3877G>A variant is predicted to result in the amino acid substitution p.Asp1293Asn. This variant was reported in the homozygous state in an individual with male infertility and morphological abnormalities of the sperm flagella (P6, Ben Khelifa et al. 2014. PubMed ID: 24360805). This variant is reported in 0.045% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-52391648-G-A). 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	-0.39	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Benign	0.020
Eigen_PC	Benign	0.098
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.73
Sift	Benign	0.22	T
Sift4G	Benign	0.32	T
Vest4		0.83
MVP		0.58
MPC		0.15
ClinPred		0.038	T
GERP RS		5.3
gMVP		0.17

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

LitVar

Other links and lift over

dbSNP: rs140883175; hg19: chr3-52391648;