3-52344554-A-G

Variant names:

• chr3-52344554-A-G
• rs76591348
• NM_015512.5:c.1351A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015512.5(DNAH1):​c.1351A>G​(p.Lys451Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00116 in 1,614,012 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (6 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 4.50
• Publications: 5 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010901868).
• BP6: Variant 3-52344554-A-G is Benign according to our data. Variant chr3-52344554-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 290747.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00117 (1716/1461674) while in subpopulation MID AF = 0.00433 (25/5768). AF 95% confidence interval is 0.00301. There are 6 homozygotes in GnomAdExome4. There are 876 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015512.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH1	NM_015512.5	MANE Select	c.1351A>G	p.Lys451Glu	missense	Exon 9 of 78	NP_056327.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH1	ENST00000420323.7	TSL:1 MANE Select	c.1351A>G	p.Lys451Glu	missense	Exon 9 of 78	ENSP00000401514.2
	DNAH1	ENST00000486752.5	TSL:2	n.1612A>G		non_coding_transcript_exon	Exon 9 of 77
	DNAH1	ENST00000497875.1	TSL:2	n.1516A>G		non_coding_transcript_exon	Exon 10 of 21

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00162

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000967 AC: 241 AN: 249242 AF XY: 0.000991

Gnomad AFR exome AF: 0.000387

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.00447

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00129

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.00117 AC: 1716 AN: 1461674 Hom.: 6 Cov.: 31 AF XY: 0.00120 AC XY: 876 AN XY: 727126

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.000425 AC: 19 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 128 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000754 AC: 65 AN: 86258

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53402

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.00124 AC: 1382 AN: 1111844

Other (OTH) AF: 0.00124 AC: 75 AN: 60368

GnomAD4 genome AF: 0.00104 AC: 159 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000873 AC XY: 65 AN XY: 74494

African (AFR) AF: 0.000216 AC: 9 AN: 41584

American (AMR) AF: 0.000457 AC: 7 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00606 AC: 21 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00160 AC: 109 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.000963

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000238 AC: 1

ESP6500EA AF: 0.00154 AC: 13

ExAC AF: 0.00103 AC: 125

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Aug 25, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 20, 2023

Revvity Omics, Revvity

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 31, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNAH1-related disorder Benign:1

Jan 04, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	23
DANN	Uncertain	1.0
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
PhyloP100		4.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.057
Sift	Benign	0.23	T
Sift4G	Benign	0.44	T
Vest4		0.54
MVP		0.35
MPC		0.19
ClinPred		0.016	T
GERP RS		5.0
gMVP		0.56
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs76591348; hg19: chr3-52378570; COSMIC: COSV70233272;