rs370624357

Positions:

chr3-52396468-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_015512.5(DNAH1):c.11360G>A(p.Arg3787His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000499 in 1,602,478 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.38

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29627347).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5 linkuse as main transcript	c.11360G>A	p.Arg3787His	missense_variant	71/78	ENST00000420323.7	NP_056327.4	Q9P2D7-4A0A140VJI6
DNAH1	XM_017006129.2 linkuse as main transcript	c.11429G>A	p.Arg3810His	missense_variant	73/80		XP_016861618.1
DNAH1	XM_017006130.2 linkuse as main transcript	c.11360G>A	p.Arg3787His	missense_variant	72/79		XP_016861619.1	Q9P2D7-4A0A140VJI6
DNAH1	XM_017006131.2 linkuse as main transcript	c.11303G>A	p.Arg3768His	missense_variant	72/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DNAH1	ENST00000420323.7 linkuse as main transcript	c.11360G>A	p.Arg3787His	missense_variant	71/78	1	NM_015512.5	ENSP00000401514.2	Q9P2D7-4
DNAH1	ENST00000486752.5 linkuse as main transcript	n.11817G>A		non_coding_transcript_exon_variant	70/77	2
DNAH1	ENST00000488988.5 linkuse as main transcript	n.3146G>A		non_coding_transcript_exon_variant	18/25	2
DNAH1	ENST00000490713.5 linkuse as main transcript	n.2060G>A		non_coding_transcript_exon_variant	14/20	5		ENSP00000419071.1	H7C563

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000677

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000829

AC:

AN:

229104

Hom.:

AF XY:

0.0000965

AC XY:

AN XY:

124378

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000106

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000194

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000338

AC:

AN:

1450388

Hom.:

Cov.:

AF XY:

0.0000319

AC XY:

AN XY:

720496

show subpopulations

Gnomad4 AFR exome

AF:

0.000962

Gnomad4 AMR exome

AF:

0.0000465

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000712

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000542

Gnomad4 OTH exome

AF:

0.0000500

GnomAD4 genome

AF:

0.000204

AC:

AN:

152090

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74280

show subpopulations

Gnomad4 AFR

AF:

0.000677

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000315

Hom.:

Bravo

AF:

0.000234

ESP6500AA

AF:

0.000235

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000124

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2024

The c.11360G>A (p.R3787H) alteration is located in exon 71 (coding exon 70) of the DNAH1 gene. This alteration results from a G to A substitution at nucleotide position 11360, causing the arginine (R) at amino acid position 3787 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 20, 2022

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 3787 of the DNAH1 protein (p.Arg3787His). This variant is present in population databases (rs370624357, 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: 478397). 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: "Probably 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Pathogenic

1.0

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.76

M_CAP

Benign

0.040

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.92

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.8

REVEL

Benign

0.19

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.014

Vest4

0.61

MVP

0.52

MPC

0.62

ClinPred

0.45

GERP RS

4.3

gMVP

0.55

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