3-52353584-G-A

Position:

chr3-52353584-G-A

Variant summary

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

The NM_015512.5(DNAH1):c.3431G>A(p.Ser1144Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,611,696 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. S1144S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

DNAH1
NM_015512.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.35

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 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=0.07127133).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DNAH1	NM_015512.5 linkuse as main transcript	c.3431G>A	p.Ser1144Asn	missense_variant	20/78	ENST00000420323.7
DNAH1	XM_017006129.2 linkuse as main transcript	c.3431G>A	p.Ser1144Asn	missense_variant	21/80
DNAH1	XM_017006130.2 linkuse as main transcript	c.3431G>A	p.Ser1144Asn	missense_variant	21/79
DNAH1	XM_017006131.2 linkuse as main transcript	c.3431G>A	p.Ser1144Asn	missense_variant	21/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7 linkuse as main transcript	c.3431G>A	p.Ser1144Asn	missense_variant	20/78	1	NM_015512.5	P1	Q9P2D7-4
DNAH1	ENST00000486752.5 linkuse as main transcript	n.3692G>A		non_coding_transcript_exon_variant	20/77	2
DNAH1	ENST00000497875.1 linkuse as main transcript	n.3596G>A		non_coding_transcript_exon_variant	21/21	2

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000229

AC:

AN:

244074

Hom.:

AF XY:

0.000234

AC XY:

AN XY:

132548

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000471

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000400

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000217

Gnomad OTH exome

AF:

0.000676

GnomAD4 exome

AF:

0.000210

AC:

306

AN:

1459352

Hom.:

Cov.:

AF XY:

0.000238

AC XY:

173

AN XY:

725794

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000586

Gnomad4 ASJ exome

AF:

0.0000768

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000466

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000190

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000138

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000162

ExAC

AF:

0.000239

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: c.3431_3432delinsAT (p.Ser1144Asn). Missense variant, not reported previously. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 15, 2021	The c.3431G>A (p.S1144N) alteration is located in exon 20 (coding exon 19) of the DNAH1 gene. This alteration results from a G to A substitution at nucleotide position 3431, causing the serine (S) at amino acid position 1144 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.97

Eigen

Benign

-0.014

Eigen_PC

Benign

0.16

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.79

M_CAP

Benign

0.0082

MetaRNN

Benign

0.071

MetaSVM

Benign

-0.93

MutationTaster

Benign

0.96

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.5

REVEL

Benign

0.042

Sift

Benign

0.49

Sift4G

Benign

0.53

Vest4

0.48

MVP

0.53

MPC

0.19

ClinPred

0.026

GERP RS

3.9

gMVP

0.38

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