NM_015512.5:c.2919C>T

Variant names:

• chr3-52352599-C-T
• rs149114984
• NM_015512.5:c.2919C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015512.5(DNAH1):​c.2919C>T​(p.His973His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00539 in 1,612,762 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (38 hom.)
• Consequence: DNAH1 NM_015512.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.414
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 3-52352599-C-T is Benign according to our data. Variant chr3-52352599-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 478435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.414 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00445 (674/151398) while in subpopulation NFE AF = 0.00713 (484/67852). AF 95% confidence interval is 0.00661. There are 4 homozygotes in GnomAd4. There are 317 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.2919C>T	p.His973His	synonymous_variant	Exon 18 of 78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.2919C>T	p.His973His	synonymous_variant	Exon 19 of 80		XP_016861618.1
DNAH1	XM_017006130.2	c.2919C>T	p.His973His	synonymous_variant	Exon 19 of 79		XP_016861619.1
DNAH1	XM_017006131.2	c.2919C>T	p.His973His	synonymous_variant	Exon 19 of 79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.2919C>T	p.His973His	synonymous_variant	Exon 18 of 78	1	NM_015512.5	ENSP00000401514.2
DNAH1	ENST00000486752.5	n.3180C>T		non_coding_transcript_exon_variant	Exon 18 of 77	2
DNAH1	ENST00000497875.1	n.3084C>T		non_coding_transcript_exon_variant	Exon 19 of 21	2

Frequencies

GnomAD3 genomes AF: 0.00446 AC: 675 AN: 151280 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000973

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00324

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.00566

Gnomad FIN AF: 0.00554

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00713

Gnomad OTH AF: 0.00386

GnomAD2 exomes AF: 0.00489 AC: 1218 AN: 249070 AF XY: 0.00508

Gnomad AFR exome AF: 0.000840

Gnomad AMR exome AF: 0.00258

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00641

Gnomad NFE exome AF: 0.00636

Gnomad OTH exome AF: 0.00463

GnomAD4 exome AF: 0.00549 AC: 8021 AN: 1461364 Hom.: 38 Cov.: 32 AF XY: 0.00560 AC XY: 4068 AN XY: 726986

African (AFR) AF: 0.000627 AC: 21 AN: 33480

American (AMR) AF: 0.00250 AC: 112 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 37 AN: 26136

East Asian (EAS) AF: 0.000328 AC: 13 AN: 39694

South Asian (SAS) AF: 0.00708 AC: 611 AN: 86254

European-Finnish (FIN) AF: 0.00793 AC: 422 AN: 53184

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.00586 AC: 6515 AN: 1111762

Other (OTH) AF: 0.00461 AC: 278 AN: 60368

GnomAD4 genome AF: 0.00445 AC: 674 AN: 151398 Hom.: 4 Cov.: 32 AF XY: 0.00429 AC XY: 317 AN XY: 73954

African (AFR) AF: 0.000970 AC: 40 AN: 41228

American (AMR) AF: 0.00324 AC: 49 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3464

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5174

South Asian (SAS) AF: 0.00546 AC: 26 AN: 4766

European-Finnish (FIN) AF: 0.00554 AC: 58 AN: 10470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00713 AC: 484 AN: 67852

Other (OTH) AF: 0.00382 AC: 8 AN: 2096

Alfa AF: 0.00553 Hom.: 4

Bravo AF: 0.00381

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00605

EpiControl AF: 0.00522

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNAH1: BP4, BP7, BS2 -

DNAH1-related disorder Benign:1

Nov 05, 2019

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.9
DANN	Benign	0.47
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism

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: rs149114984; hg19: chr3-52386615; COSMIC: COSV70236615;