3-52350578-A-G

Position:

chr3-52350578-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015512.5(DNAH1):c.2717A>G(p.Asp906Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00691 in 1,613,708 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0072 ( 47 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:3

Conservation

PhyloP100: 7.67

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008781254).

BP6

Variant 3-52350578-A-G is Benign according to our data. Variant chr3-52350578-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 478433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00412 (627/152284) while in subpopulation NFE AF= 0.00753 (512/68016). AF 95% confidence interval is 0.00699. There are 4 homozygotes in gnomad4. There are 287 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DNAH1	NM_015512.5 linkuse as main transcript	c.2717A>G	p.Asp906Gly	missense_variant	16/78	ENST00000420323.7
DNAH1	XM_017006129.2 linkuse as main transcript	c.2717A>G	p.Asp906Gly	missense_variant	17/80
DNAH1	XM_017006130.2 linkuse as main transcript	c.2717A>G	p.Asp906Gly	missense_variant	17/79
DNAH1	XM_017006131.2 linkuse as main transcript	c.2717A>G	p.Asp906Gly	missense_variant	17/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7 linkuse as main transcript	c.2717A>G	p.Asp906Gly	missense_variant	16/78	1	NM_015512.5	P1	Q9P2D7-4
DNAH1	ENST00000486752.5 linkuse as main transcript	n.2978A>G		non_coding_transcript_exon_variant	16/77	2
DNAH1	ENST00000497875.1 linkuse as main transcript	n.2882A>G		non_coding_transcript_exon_variant	17/21	2

Frequencies

GnomAD3 genomes

AF:

0.00412

AC:

627

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00150

Gnomad ASJ

AF:

0.00635

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00264

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00753

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00445

AC:

1106

AN:

248652

Hom.:

AF XY:

0.00423

AC XY:

571

AN XY:

134896

show subpopulations

Gnomad AFR exome

AF:

0.000844

Gnomad AMR exome

AF:

0.00209

Gnomad ASJ exome

AF:

0.00458

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00451

Gnomad NFE exome

AF:

0.00755

Gnomad OTH exome

AF:

0.00430

GnomAD4 exome

AF:

0.00720

AC:

10527

AN:

1461424

Hom.:

Cov.:

AF XY:

0.00691

AC XY:

5022

AN XY:

726972

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.00190

Gnomad4 ASJ exome

AF:

0.00528

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00436

Gnomad4 NFE exome

AF:

0.00864

Gnomad4 OTH exome

AF:

0.00704

GnomAD4 genome

AF:

0.00412

AC:

627

AN:

152284

Hom.:

Cov.:

AF XY:

0.00385

AC XY:

287

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.000890

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.00635

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00264

Gnomad4 NFE

AF:

0.00753

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00679

Hom.:

Bravo

AF:

0.00397

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.000738

AC:

ESP6500EA

AF:

0.00690

AC:

ExAC

AF:

0.00438

AC:

530

EpiCase

AF:

0.00883

EpiControl

AF:

0.00730

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	DNAH1: BS2 -

Premature ovarian insufficiency

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Reproductive Development, Murdoch Childrens Research Institute

Jan 10, 2018

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.025

MetaRNN

Benign

0.0088

MetaSVM

Benign

-0.80

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-5.3

REVEL

Uncertain

0.37

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0070

Vest4

0.75

MVP

0.45

MPC

0.28

ClinPred

0.026

GERP RS

4.7

gMVP

0.87

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