rs200067536

Positions:

chr3-52332192-C-T

Variant summary

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

The NM_015512.5(DNAH1):c.1084C>T(p.Leu362Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,599,966 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00071 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 1 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.29

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 -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09273377).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DNAH1	NM_015512.5 linkuse as main transcript	c.1084C>T	p.Leu362Phe	missense_variant	8/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2 linkuse as main transcript	c.1084C>T	p.Leu362Phe	missense_variant	9/80		XP_016861618.1
DNAH1	XM_017006130.2 linkuse as main transcript	c.1084C>T	p.Leu362Phe	missense_variant	9/79		XP_016861619.1
DNAH1	XM_017006131.2 linkuse as main transcript	c.1084C>T	p.Leu362Phe	missense_variant	9/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7 linkuse as main transcript	c.1084C>T	p.Leu362Phe	missense_variant	8/78	1	NM_015512.5	ENSP00000401514	P1	Q9P2D7-4
DNAH1	ENST00000486752.5 linkuse as main transcript	n.1345C>T		non_coding_transcript_exon_variant	8/77	2
DNAH1	ENST00000497875.1 linkuse as main transcript	n.1249C>T		non_coding_transcript_exon_variant	9/21	2

Frequencies

GnomAD3 genomes

AF:

0.000709

AC:

108

AN:

152258

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00212

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

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:

0.000956

GnomAD3 exomes

AF:

0.0000882

AC:

AN:

226730

Hom.:

AF XY:

0.0000897

AC XY:

AN XY:

122626

show subpopulations

Gnomad AFR exome

AF:

0.00104

Gnomad AMR exome

AF:

0.0000946

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:

0.000531

GnomAD4 exome

AF:

0.0000470

AC:

AN:

1447708

Hom.:

Cov.:

AF XY:

0.0000459

AC XY:

AN XY:

718858

show subpopulations

Gnomad4 AFR exome

AF:

0.00117

Gnomad4 AMR exome

AF:

0.000308

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:

0.000217

GnomAD4 genome

AF:

0.000709

AC:

108

AN:

152258

Hom.:

Cov.:

AF XY:

0.000605

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.00212

Gnomad4 AMR

AF:

0.00118

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:

0.000956

Alfa

AF:

0.000329

Hom.:

Bravo

AF:

0.000827

ESP6500AA

AF:

0.00144

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000116

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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 18, 2023

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 362 of the DNAH1 protein (p.Leu362Phe). This variant is present in population databases (rs200067536, gnomAD 0.1%). 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: 544603). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.84

M_CAP

Benign

0.012

MetaRNN

Benign

0.093

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.9

REVEL

Benign

0.21

Sift

Benign

0.31

Sift4G

Benign

0.46

Vest4

0.57

MVP

0.59

MPC

0.32

ClinPred

0.071

GERP RS

5.9

gMVP

0.38

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