rs199602894

Variant names:

• chr3-52386735-A-C
• rs199602894
• NM_015512.5:c.8885A>C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Moderate BP6 BS1

The NM_015512.5(DNAH1):​c.8885A>C​(p.Lys2962Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000391 in 1,589,858 control chromosomes in the GnomAD database, including 1 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 0.00047 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (1 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 7.30

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 Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07671729).
• BP6: Variant 3-52386735-A-C is Benign according to our data. Variant chr3-52386735-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 478506.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000383 (550/1437522) while in subpopulation MID AF= 0.00696 (40/5744). AF 95% confidence interval is 0.00526. There are 1 homozygotes in gnomad4_exome. There are 271 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.8885A>C	p.Lys2962Thr	missense_variant	Exon 56 of 78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.8954A>C	p.Lys2985Thr	missense_variant	Exon 58 of 80		XP_016861618.1
DNAH1	XM_017006130.2	c.8885A>C	p.Lys2962Thr	missense_variant	Exon 57 of 79		XP_016861619.1
DNAH1	XM_017006131.2	c.8954A>C	p.Lys2985Thr	missense_variant	Exon 58 of 79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.8885A>C	p.Lys2962Thr	missense_variant	Exon 56 of 78	1	NM_015512.5	ENSP00000401514.2
DNAH1	ENST00000486752.5	n.9146A>C		non_coding_transcript_exon_variant	Exon 56 of 77	2
DNAH1	ENST00000488988.5	n.475A>C		non_coding_transcript_exon_variant	Exon 4 of 25	2

Frequencies

GnomAD3 genomes AF: 0.000466 AC: 71 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000432 AC: 89 AN: 205990 Hom.: 0 AF XY: 0.000449 AC XY: 50 AN XY: 111396

Gnomad AFR exome AF: 0.0000880

Gnomad AMR exome AF: 0.000671

Gnomad ASJ exome AF: 0.00175

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000156

Gnomad FIN exome AF: 0.000157

Gnomad NFE exome AF: 0.000420

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000383 AC: 550 AN: 1437522 Hom.: 1 Cov.: 31 AF XY: 0.000380 AC XY: 271 AN XY: 712656

Gnomad4 AFR exome AF: 0.00103

Gnomad4 AMR exome AF: 0.000755

Gnomad4 ASJ exome AF: 0.00203

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000146

Gnomad4 FIN exome AF: 0.0000388

Gnomad4 NFE exome AF: 0.000298

Gnomad4 OTH exome AF: 0.000856

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.000524 AC XY: 39 AN XY: 74488

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000475 Hom.: 0

Bravo AF: 0.000661

ESP6500AA AF: 0.000513 AC: 2

ESP6500EA AF: 0.000846 AC: 7

ExAC AF: 0.000457 AC: 55

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Dec 15, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID# 478506; ClinVar) -

Feb 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DNAH1 c.8885A>C; p.Lys2962Thr variant (rs199602894), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 478506). This variant is observed in the general population with an overall allele frequency of 0.04% (94/237354 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.515). Due to limited information, the clinical significance of this variant is uncertain at this time. -

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

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DNAH1-related disorder Benign:1

Dec 01, 2022

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
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.077	T
MetaSVM	Uncertain	0.35	D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.076	T
Vest4		0.50
MVP		0.62
MPC		0.60
ClinPred		0.10	T
GERP RS		4.2
gMVP		0.70

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: rs199602894; hg19: chr3-52420751;