rs12163565

Variant names:

• chr3-52396510-G-A
• rs12163565
• NM_015512.5:c.11402G>A

Variant summary

Our verdict is Benign. The variant received -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. 14/19 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:6
• Conservation: PhyloP100: 2.05
• Publications: 32 publications found

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 Gene-Disease associations (from GenCC):

• spermatogenic failure 18

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• ciliary dyskinesia, primary, 37

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic male infertility due to sperm motility disorder

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.11402G>A	p.Gly3801Asp	missense_variant	Exon 71 of 78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.11471G>A	p.Gly3824Asp	missense_variant	Exon 73 of 80		XP_016861618.1
DNAH1	XM_017006130.2	c.11402G>A	p.Gly3801Asp	missense_variant	Exon 72 of 79		XP_016861619.1
DNAH1	XM_017006131.2	c.11345G>A	p.Gly3782Asp	missense_variant	Exon 72 of 79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.11402G>A	p.Gly3801Asp	missense_variant	Exon 71 of 78	1	NM_015512.5	ENSP00000401514.2
DNAH1	ENST00000486752.5	n.11859G>A		non_coding_transcript_exon_variant	Exon 70 of 77	2
DNAH1	ENST00000488988.5	n.3188G>A		non_coding_transcript_exon_variant	Exon 18 of 25	2
DNAH1	ENST00000490713.5	n.2102G>A		non_coding_transcript_exon_variant	Exon 14 of 20	5		ENSP00000419071.1

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

GnomAD2 exomes AF: 0.193 AC: 46753 AN: 242176 AF XY: 0.200

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 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

African (AFR) AF: 0.0371 AC: 1240 AN: 33428

American (AMR) AF: 0.0976 AC: 4313 AN: 44174

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 5786 AN: 26064

East Asian (EAS) AF: 0.200 AC: 7892 AN: 39514

South Asian (SAS) AF: 0.235 AC: 20179 AN: 85800

European-Finnish (FIN) AF: 0.260 AC: 13733 AN: 52860

Middle Eastern (MID) AF: 0.223 AC: 1286 AN: 5766

European-Non Finnish (NFE) AF: 0.204 AC: 226450 AN: 1110108

Other (OTH) AF: 0.207 AC: 12475 AN: 60236

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

African (AFR) AF: 0.0469 AC: 1946 AN: 41534

American (AMR) AF: 0.140 AC: 2136 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 764 AN: 3472

East Asian (EAS) AF: 0.269 AC: 1388 AN: 5154

South Asian (SAS) AF: 0.228 AC: 1100 AN: 4816

European-Finnish (FIN) AF: 0.254 AC: 2686 AN: 10564

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13810 AN: 67976

Other (OTH) AF: 0.171 AC: 361 AN: 2106

Alfa AF: 0.188 Hom.: 10034

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spermatogenic failure 18 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		2.1
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
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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