rs200013928

Positions:

chr3-52332195-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015512.5(DNAH1):c.1087T>C(p.Phe363Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000905 in 1,602,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 6.81

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:

DNAH1 (HGNC:):

DNAH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.20447701).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5 linkuse as main transcript	c.1087T>C	p.Phe363Leu	missense_variant	8/78	ENST00000420323.7	NP_056327.4	Q9P2D7-4A0A140VJI6
DNAH1	XM_017006129.2 linkuse as main transcript	c.1087T>C	p.Phe363Leu	missense_variant	9/80		XP_016861618.1
DNAH1	XM_017006130.2 linkuse as main transcript	c.1087T>C	p.Phe363Leu	missense_variant	9/79		XP_016861619.1	Q9P2D7-4A0A140VJI6
DNAH1	XM_017006131.2 linkuse as main transcript	c.1087T>C	p.Phe363Leu	missense_variant	9/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DNAH1	ENST00000420323.7 linkuse as main transcript	c.1087T>C	p.Phe363Leu	missense_variant	8/78	1	NM_015512.5	ENSP00000401514.2	Q9P2D7-4
DNAH1	ENST00000486752.5 linkuse as main transcript	n.1348T>C		non_coding_transcript_exon_variant	8/77	2
DNAH1	ENST00000497875.1 linkuse as main transcript	n.1252T>C		non_coding_transcript_exon_variant	9/21	2

Frequencies

GnomAD3 genomes

AF:

0.000525

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00188

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000130

AC:

AN:

230940

Hom.:

AF XY:

0.000104

AC XY:

AN XY:

124952

show subpopulations

Gnomad AFR exome

AF:

0.00188

Gnomad AMR exome

AF:

0.0000620

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:

0.00000965

Gnomad OTH exome

AF:

0.000175

GnomAD4 exome

AF:

0.0000427

AC:

AN:

1450342

Hom.:

Cov.:

AF XY:

0.0000361

AC XY:

AN XY:

720408

show subpopulations

Gnomad4 AFR exome

AF:

0.00150

Gnomad4 AMR exome

AF:

0.0000938

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:

0.00000181

Gnomad4 OTH exome

AF:

0.0000833

GnomAD4 genome

AF:

0.000545

AC:

AN:

152364

Hom.:

Cov.:

AF XY:

0.000510

AC XY:

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.00195

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000107

Hom.:

Bravo

AF:

0.000669

ESP6500AA

AF:

0.00192

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000157

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2023

The c.1087T>C (p.F363L) alteration is located in exon 8 (coding exon 7) of the DNAH1 gene. This alteration results from a T to C substitution at nucleotide position 1087, causing the phenylalanine (F) at amino acid position 363 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 31, 2024

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 -

DNAH1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 20, 2023

The DNAH1 c.1087T>C variant is predicted to result in the amino acid substitution p.Phe363Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.19% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-52366211-T-C), which may be high to be an undocumented cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Uncertain

0.99

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.028

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.74

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-4.6

REVEL

Uncertain

0.34

Sift

Benign

0.14

Sift4G

Benign

0.14

Vest4

0.78

MutPred

0.70

Gain of loop (P = 0.0166);

MVP

0.68

MPC

0.26

ClinPred

0.12

GERP RS

5.9

gMVP

0.71

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