3-52372236-A-G

Position:

chr3-52372236-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.6676A>G(p.Ile2226Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00696 in 1,613,864 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0053 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0071 ( 48 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.910

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011133552).

BP6

Variant 3-52372236-A-G is Benign according to our data. Variant chr3-52372236-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 478481.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 = 0.00528 (804/152294) while in subpopulation NFE AF= 0.00831 (565/68016). AF 95% confidence interval is 0.00774. There are 7 homozygotes in gnomad4. There are 393 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5 linkuse as main transcript	c.6676A>G	p.Ile2226Val	missense_variant	43/78	ENST00000420323.7	NP_056327.4	Q9P2D7-4A0A140VJI6
DNAH1	XM_017006129.2 linkuse as main transcript	c.6745A>G	p.Ile2249Val	missense_variant	45/80		XP_016861618.1
DNAH1	XM_017006130.2 linkuse as main transcript	c.6676A>G	p.Ile2226Val	missense_variant	44/79		XP_016861619.1	Q9P2D7-4A0A140VJI6
DNAH1	XM_017006131.2 linkuse as main transcript	c.6745A>G	p.Ile2249Val	missense_variant	45/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7 linkuse as main transcript	c.6676A>G	p.Ile2226Val	missense_variant	43/78	1	NM_015512.5	ENSP00000401514.2		Q9P2D7-4
DNAH1	ENST00000486752.5 linkuse as main transcript	n.6937A>G		non_coding_transcript_exon_variant	43/77	2

Frequencies

GnomAD3 genomes

AF:

0.00528

AC:

803

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.0429

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00606

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00455

Gnomad FIN

AF:

0.00574

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00831

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00557

AC:

1385

AN:

248732

Hom.:

AF XY:

0.00592

AC XY:

799

AN XY:

134994

show subpopulations

Gnomad AFR exome

AF:

0.00104

Gnomad AMR exome

AF:

0.00215

Gnomad ASJ exome

AF:

0.00578

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.00549

Gnomad FIN exome

AF:

0.00684

Gnomad NFE exome

AF:

0.00792

Gnomad OTH exome

AF:

0.00464

GnomAD4 exome

AF:

0.00714

AC:

10433

AN:

1461570

Hom.:

Cov.:

AF XY:

0.00718

AC XY:

5223

AN XY:

727074

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.00237

Gnomad4 ASJ exome

AF:

0.00624

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00580

Gnomad4 FIN exome

AF:

0.00633

Gnomad4 NFE exome

AF:

0.00794

Gnomad4 OTH exome

AF:

0.00726

GnomAD4 genome

AF:

0.00528

AC:

804

AN:

152294

Hom.:

Cov.:

AF XY:

0.00528

AC XY:

393

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00123

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.00606

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00455

Gnomad4 FIN

AF:

0.00574

Gnomad4 NFE

AF:

0.00831

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00731

Hom.:

Bravo

AF:

0.00484

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.00117

AC:

ESP6500EA

AF:

0.00868

AC:

ExAC

AF:

0.00580

AC:

703

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.00714

EpiControl

AF:

0.00871

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely 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	Nov 01, 2024	DNAH1: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Benign

8.6

DANN

Benign

0.68

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.82

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.96

PrimateAI

Benign

0.29

PROVEAN

Benign

0.15

REVEL

Benign

0.017

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.27

MVP

0.13

MPC

0.10

ClinPred

0.000035

GERP RS

1.9

gMVP

0.29

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