NM_015512.5:c.3877G>A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: 4.91

Variant links:

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]

DNAH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

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

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000368 (56/152214) while in subpopulation AMR AF= 0.00196 (30/15286). AF 95% confidence interval is 0.00141. There are 1 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH1	NM_015512.5 link	c.3877G>A	p.Asp1293Asn	missense_variant	Exon 23 of 78	ENST00000420323.7	NP_056327.4	Q9P2D7-4A0A140VJI6
DNAH1	XM_017006129.2 link	c.3877G>A	p.Asp1293Asn	missense_variant	Exon 24 of 80		XP_016861618.1
DNAH1	XM_017006130.2 link	c.3877G>A	p.Asp1293Asn	missense_variant	Exon 24 of 79		XP_016861619.1	Q9P2D7-4A0A140VJI6
DNAH1	XM_017006131.2 link	c.3877G>A	p.Asp1293Asn	missense_variant	Exon 24 of 79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7 link	c.3877G>A	p.Asp1293Asn	missense_variant	Exon 23 of 78	1	NM_015512.5	ENSP00000401514.2		Q9P2D7-4
DNAH1	ENST00000486752.5 link	n.4138G>A		non_coding_transcript_exon_variant	Exon 23 of 77	2

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

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:

AN:

228418

Hom.:

AF XY:

0.000226

AC XY:

AN XY:

123706

show subpopulations

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.:

Cov.:

AF XY:

0.000202

AC XY:

145

AN XY:

719300

show subpopulations

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:

AN:

152214

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74416

show subpopulations

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.:

Bravo

AF:

0.000756

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000244

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000149

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spermatogenic failure 18

Pathogenic:1

Jul 20, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Uncertain:1

Dec 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 07, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

1.0

Eigen

Benign

0.020

Eigen_PC

Benign

0.098

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.80

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.88

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.7

REVEL

Pathogenic

0.73

Sift

Benign

0.22

Sift4G

Benign

0.32

Vest4

0.83

MVP

0.58

MPC

0.15

ClinPred

0.038

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over