rs12163565

chr3-52396510-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015512.5(DNAH1):c.11402G>A(p.Gly3801Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 1,610,062 control chromosomes in the GnomAD database, including 33,361 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2538 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30823 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.05

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051918626).
• BP6: Variant 3-52396510-G-A is Benign according to our data. Variant chr3-52396510-G-A is described in ClinVar as [Benign]. Clinvar id is 402604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.11402G>A	p.Gly3801Asp	missense_variant	71/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.11471G>A	p.Gly3824Asp	missense_variant	73/80
DNAH1	XM_017006130.2	c.11402G>A	p.Gly3801Asp	missense_variant	72/79
DNAH1	XM_017006131.2	c.11345G>A	p.Gly3782Asp	missense_variant	72/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.11402G>A	p.Gly3801Asp	missense_variant	71/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.11859G>A		non_coding_transcript_exon_variant	70/77	2
DNAH1	ENST00000488988.5	n.3188G>A		non_coding_transcript_exon_variant	18/25	2
DNAH1	ENST00000490713.5	c.2102G>A	p.Gly701Asp	missense_variant, NMD_transcript_variant	14/20	5

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24503 AN: 151994 Hom.: 2539 Cov.: 32

Gnomad AFR AF: 0.0469

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.173

GnomAD3 exomes AF: 0.193 AC: 46753 AN: 242176 Hom.: 5005 AF XY: 0.200 AC XY: 26313 AN XY: 131590

Gnomad AFR exome AF: 0.0445

Gnomad AMR exome AF: 0.0935

Gnomad ASJ exome AF: 0.225

Gnomad EAS exome AF: 0.270

Gnomad SAS exome AF: 0.233

Gnomad FIN exome AF: 0.260

Gnomad NFE exome AF: 0.204

Gnomad OTH exome AF: 0.209

GnomAD4 exome AF: 0.201 AC: 293354 AN: 1457950 Hom.: 30823 Cov.: 36 AF XY: 0.204 AC XY: 147697 AN XY: 724932

Gnomad4 AFR exome AF: 0.0371

Gnomad4 AMR exome AF: 0.0976

Gnomad4 ASJ exome AF: 0.222

Gnomad4 EAS exome AF: 0.200

Gnomad4 SAS exome AF: 0.235

Gnomad4 FIN exome AF: 0.260

Gnomad4 NFE exome AF: 0.204

Gnomad4 OTH exome AF: 0.207

GnomAD4 genome AF: 0.161 AC: 24499 AN: 152112 Hom.: 2538 Cov.: 32 AF XY: 0.165 AC XY: 12280 AN XY: 74334

Gnomad4 AFR AF: 0.0469

Gnomad4 AMR AF: 0.140

Gnomad4 ASJ AF: 0.220

Gnomad4 EAS AF: 0.269

Gnomad4 SAS AF: 0.228

Gnomad4 FIN AF: 0.254

Gnomad4 NFE AF: 0.203

Gnomad4 OTH AF: 0.171

Alfa AF: 0.197 Hom.: 6445

Bravo AF: 0.147

TwinsUK AF: 0.210 AC: 778

ALSPAC AF: 0.201 AC: 773

ESP6500AA AF: 0.0478 AC: 203

ESP6500EA AF: 0.189 AC: 1603

ExAC AF: 0.191 AC: 23105

Asia WGS AF: 0.209 AC: 728 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not specified Benign:1

Benign, 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: Frequency -

Ciliary dyskinesia, primary, 37 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Spermatogenic failure 18 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	17
Dann	Benign	0.63
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.74
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.51	N
REVEL	Benign	0.041
Sift	Benign	0.69	T
Sift4G	Benign	1.0	T
Vest4		0.083
MPC		0.16
ClinPred		0.00093	T
GERP RS		2.4
gMVP		0.41

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

Other links and lift over

dbSNP: rs12163565; hg19: chr3-52430526; COSMIC: COSV56239387; COSMIC: COSV56239387;