3-52322488-C-T

Position:

chr3-52322488-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_015512.5(DNAH1):c.46C>T(p.Gln16Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,613,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

DNAH1
NM_015512.5 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: -0.383

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_pathogenic. Variant got 7 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-52322488-C-T is Pathogenic according to our data. Variant chr3-52322488-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1453969.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DNAH1	NM_015512.5 linkuse as main transcript	c.46C>T	p.Gln16Ter	stop_gained	2/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2 linkuse as main transcript	c.46C>T	p.Gln16Ter	stop_gained	3/80		XP_016861618.1
DNAH1	XM_017006130.2 linkuse as main transcript	c.46C>T	p.Gln16Ter	stop_gained	3/79		XP_016861619.1
DNAH1	XM_017006131.2 linkuse as main transcript	c.46C>T	p.Gln16Ter	stop_gained	3/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7 linkuse as main transcript	c.46C>T	p.Gln16Ter	stop_gained	2/78	1	NM_015512.5	ENSP00000401514	P1	Q9P2D7-4
DNAH1	ENST00000486752.5 linkuse as main transcript	n.307C>T		non_coding_transcript_exon_variant	2/77	2
DNAH1	ENST00000497875.1 linkuse as main transcript	n.211C>T		non_coding_transcript_exon_variant	3/21	2

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000443

AC:

AN:

248358

Hom.:

AF XY:

0.0000445

AC XY:

AN XY:

134820

show subpopulations

Gnomad AFR exome

AF:

0.000649

Gnomad AMR exome

AF:

0.0000292

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:

0.0000130

AC:

AN:

1461158

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726876

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.0000224

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

AF:

0.000184

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000674

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000427

Hom.:

Bravo

AF:

0.000200

ESP6500AA

AF:

0.000783

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000579

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 13, 2020

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with DNAH1-related conditions. This variant is present in population databases (rs199910432, ExAC 0.07%). This sequence change creates a premature translational stop signal (p.Gln16*) in the DNAH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAH1 are known to be pathogenic (PMID: 27573432, 27798045). -

Spermatogenic failure 18

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Apr 04, 2024

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 14, 2024

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Reported among a cohort of individuals with cardiovascular disease traits; however, no detailed clinical information was provided (PMID: 31345219); This variant is associated with the following publications: (PMID: 31345219) -

DNAH1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 18, 2024

The DNAH1 c.46C>T variant is predicted to result in premature protein termination (p.Gln16*). This variant was reported in an individual with cardiovascular disease (Table S1, Glicksberg et al 2019. PubMed ID: 31345219). This variant is reported in 0.075% of alleles in individuals of African 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

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Benign

-0.31

CADD

Uncertain

DANN

Uncertain

0.97

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.020

MutationTaster

Benign

1.0

Vest4

0.16

GERP RS

-2.2

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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