chr3-52395315-A-G

Position:

chr3-52395315-A-G

Variant summary

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

The NM_015512.5(DNAH1):c.10976A>G(p.Asn3659Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000577 in 1,613,128 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000057 ( 1 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 8.70

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 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
DNAH1	NM_015512.5 linkuse as main transcript	c.10976A>G	p.Asn3659Ser	missense_variant	69/78	ENST00000420323.7
DNAH1	XM_017006129.2 linkuse as main transcript	c.11045A>G	p.Asn3682Ser	missense_variant	71/80
DNAH1	XM_017006130.2 linkuse as main transcript	c.10976A>G	p.Asn3659Ser	missense_variant	70/79
DNAH1	XM_017006131.2 linkuse as main transcript	c.10919A>G	p.Asn3640Ser	missense_variant	70/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7 linkuse as main transcript	c.10976A>G	p.Asn3659Ser	missense_variant	69/78	1	NM_015512.5	P1	Q9P2D7-4

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

151992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000967

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000887

AC:

AN:

247914

Hom.:

AF XY:

0.0000966

AC XY:

AN XY:

134552

show subpopulations

Gnomad AFR exome

AF:

0.0000655

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000501

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000623

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000575

AC:

AN:

1461136

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

726782

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000558

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000592

AC:

AN:

151992

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74226

show subpopulations

Gnomad4 AFR

AF:

0.0000967

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.0000642

ESP6500AA

AF:

0.000249

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

Dec 19, 2021

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 3659 of the DNAH1 protein (p.Asn3659Ser). This variant is present in population databases (rs376694884, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with DNAH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 544591). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

Primary ciliary dyskinesia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Jun 23, 2022

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 20, 2022

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.66

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.013

MetaRNN

Benign

0.22

MetaSVM

Benign

-1.1

MutationTaster

Benign

0.68

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.20

Sift

Uncertain

0.018

Sift4G

Uncertain

0.013

Vest4

0.41

MVP

0.39

MPC

0.27

ClinPred

0.19

GERP RS

3.7

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.26

Position offset: -3

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