rs13060192

Variant names:

• chr3-52344524-G-C
• rs13060192
• NM_015512.5:c.1321G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015512.5(DNAH1):​c.1321G>C​(p.Val441Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0439 in 1,613,970 control chromosomes in the GnomAD database, including 1,787 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (145 hom., cov: 33)
  • Exomes 𝑓: 0.045 (1642 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.45
• Publications: 13 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=0.0024633408).
• BP6: Variant 3-52344524-G-C is Benign according to our data. Variant chr3-52344524-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 478413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0364 (5544/152334) while in subpopulation AMR AF = 0.0485 (743/15306). AF 95% confidence interval is 0.0468. There are 145 homozygotes in GnomAd4. There are 2551 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 145 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.1321G>C	p.Val441Leu	missense_variant	Exon 9 of 78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.1321G>C	p.Val441Leu	missense_variant	Exon 10 of 80		XP_016861618.1
DNAH1	XM_017006130.2	c.1321G>C	p.Val441Leu	missense_variant	Exon 10 of 79		XP_016861619.1
DNAH1	XM_017006131.2	c.1321G>C	p.Val441Leu	missense_variant	Exon 10 of 79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.1321G>C	p.Val441Leu	missense_variant	Exon 9 of 78	1	NM_015512.5	ENSP00000401514.2
DNAH1	ENST00000486752.5	n.1582G>C		non_coding_transcript_exon_variant	Exon 9 of 77	2
DNAH1	ENST00000497875.1	n.1486G>C		non_coding_transcript_exon_variant	Exon 10 of 21	2

Frequencies

GnomAD3 genomes AF: 0.0364 AC: 5544 AN: 152216 Hom.: 144 Cov.: 33

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.0486

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.0227

Gnomad SAS AF: 0.0221

Gnomad FIN AF: 0.0342

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0481

Gnomad OTH AF: 0.0436

GnomAD2 exomes AF: 0.0367 AC: 9158 AN: 249218 AF XY: 0.0371

Gnomad AFR exome AF: 0.0157

Gnomad AMR exome AF: 0.0346

Gnomad ASJ exome AF: 0.0276

Gnomad EAS exome AF: 0.0179

Gnomad FIN exome AF: 0.0365

Gnomad NFE exome AF: 0.0480

Gnomad OTH exome AF: 0.0474

GnomAD4 exome AF: 0.0447 AC: 65313 AN: 1461636 Hom.: 1642 Cov.: 31 AF XY: 0.0443 AC XY: 32222 AN XY: 727114

African (AFR) AF: 0.0160 AC: 537 AN: 33480

American (AMR) AF: 0.0376 AC: 1682 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0283 AC: 740 AN: 26132

East Asian (EAS) AF: 0.0164 AC: 653 AN: 39700

South Asian (SAS) AF: 0.0206 AC: 1774 AN: 86258

European-Finnish (FIN) AF: 0.0375 AC: 2004 AN: 53400

Middle Eastern (MID) AF: 0.0383 AC: 221 AN: 5766

European-Non Finnish (NFE) AF: 0.0494 AC: 54894 AN: 1111814

Other (OTH) AF: 0.0465 AC: 2808 AN: 60370

GnomAD4 genome AF: 0.0364 AC: 5544 AN: 152334 Hom.: 145 Cov.: 33 AF XY: 0.0342 AC XY: 2551 AN XY: 74496

African (AFR) AF: 0.0158 AC: 658 AN: 41578

American (AMR) AF: 0.0485 AC: 743 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 101 AN: 3470

East Asian (EAS) AF: 0.0223 AC: 116 AN: 5192

South Asian (SAS) AF: 0.0219 AC: 106 AN: 4830

European-Finnish (FIN) AF: 0.0342 AC: 363 AN: 10626

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0481 AC: 3274 AN: 68016

Other (OTH) AF: 0.0431 AC: 91 AN: 2110

Alfa AF: 0.0463 Hom.: 141

Bravo AF: 0.0374

TwinsUK AF: 0.0496 AC: 184

ALSPAC AF: 0.0472 AC: 182

ESP6500AA AF: 0.0132 AC: 55

ESP6500EA AF: 0.0467 AC: 393

ExAC AF: 0.0358 AC: 4338

Asia WGS AF: 0.0370 AC: 127 AN: 3478

EpiCase AF: 0.0491

EpiControl AF: 0.0534

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 09, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31213628) -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
PhyloP100		4.5
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.040
Sift	Benign	0.079	T
Sift4G	Benign	0.086	T
Vest4		0.15
MutPred		0.64		Gain of sheet (P = 0.0016);
MPC		0.13
ClinPred		0.016	T
GERP RS		5.0
gMVP		0.46
Mutation Taster		=85/15	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: rs13060192; hg19: chr3-52378540; COSMIC: COSV108250757;