rs76591348

Positions:

• chr3-52344554-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 id is 290747.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome 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 gnomad4_exome. There are 876 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.1351A>G	p.Lys451Glu	missense_variant	9/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.1351A>G	p.Lys451Glu	missense_variant	10/80
DNAH1	XM_017006130.2	c.1351A>G	p.Lys451Glu	missense_variant	10/79
DNAH1	XM_017006131.2	c.1351A>G	p.Lys451Glu	missense_variant	10/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.1351A>G	p.Lys451Glu	missense_variant	9/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.1612A>G		non_coding_transcript_exon_variant	9/77	2
DNAH1	ENST00000497875.1	n.1516A>G		non_coding_transcript_exon_variant	10/21	2

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

GnomAD3 exomes AF: 0.000967 AC: 241 AN: 249242 Hom.: 0 AF XY: 0.000991 AC XY: 134 AN XY: 135204

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 SAS exome AF: 0.000784

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

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00490

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000754

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00124

Gnomad4 OTH exome AF: 0.00124

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

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00606

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00160

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00142 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

Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 20, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 31, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 25, 2016	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

DNAH1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 04, 2021

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	0.42
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
MutationTaster	Benign	0.97	D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs76591348; hg19: chr3-52378570; COSMIC: COSV70233272;