rs1546737

chr3-52373025-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_015512.5(DNAH1):c.6957C>T(p.His2319=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 1,612,634 control chromosomes in the GnomAD database, including 75,624 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5629 hom., cov: 33)
  • Exomes 𝑓: 0.30 (69995 hom.)
• Consequence: DNAH1 NM_015512.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.509

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 3-52373025-C-T is Benign according to our data. Variant chr3-52373025-C-T is described in ClinVar as [Benign]. Clinvar id is 402601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.509 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.324 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.6957C>T	p.His2319=	synonymous_variant	44/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.7026C>T	p.His2342=	synonymous_variant	46/80
DNAH1	XM_017006130.2	c.6957C>T	p.His2319=	synonymous_variant	45/79
DNAH1	XM_017006131.2	c.7026C>T	p.His2342=	synonymous_variant	46/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.6957C>T	p.His2319=	synonymous_variant	44/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.7218C>T		non_coding_transcript_exon_variant	44/77	2

Frequencies

GnomAD3 genomes AF: 0.243 AC: 36927 AN: 152112 Hom.: 5630 Cov.: 33

Gnomad AFR AF: 0.0594

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.266

Gnomad ASJ AF: 0.362

Gnomad EAS AF: 0.184

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.327

Gnomad OTH AF: 0.255

GnomAD3 exomes AF: 0.287 AC: 71059 AN: 247388 Hom.: 11067 AF XY: 0.293 AC XY: 39377 AN XY: 134424

Gnomad AFR exome AF: 0.0516

Gnomad AMR exome AF: 0.250

Gnomad ASJ exome AF: 0.371

Gnomad EAS exome AF: 0.167

Gnomad SAS exome AF: 0.260

Gnomad FIN exome AF: 0.362

Gnomad NFE exome AF: 0.335

Gnomad OTH exome AF: 0.307

GnomAD4 exome AF: 0.305 AC: 445084 AN: 1460404 Hom.: 69995 Cov.: 37 AF XY: 0.305 AC XY: 221469 AN XY: 726510

Gnomad4 AFR exome AF: 0.0447

Gnomad4 AMR exome AF: 0.252

Gnomad4 ASJ exome AF: 0.371

Gnomad4 EAS exome AF: 0.259

Gnomad4 SAS exome AF: 0.256

Gnomad4 FIN exome AF: 0.360

Gnomad4 NFE exome AF: 0.317

Gnomad4 OTH exome AF: 0.283

GnomAD4 genome AF: 0.243 AC: 36930 AN: 152230 Hom.: 5629 Cov.: 33 AF XY: 0.244 AC XY: 18168 AN XY: 74416

Gnomad4 AFR AF: 0.0592

Gnomad4 AMR AF: 0.266

Gnomad4 ASJ AF: 0.362

Gnomad4 EAS AF: 0.185

Gnomad4 SAS AF: 0.265

Gnomad4 FIN AF: 0.352

Gnomad4 NFE AF: 0.327

Gnomad4 OTH AF: 0.256

Alfa AF: 0.309 Hom.: 9932

Bravo AF: 0.224

Asia WGS AF: 0.236 AC: 821 AN: 3478

EpiCase AF: 0.332

EpiControl AF: 0.330

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
Cadd	Benign	4.5
Dann	Benign	0.92

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: rs1546737; hg19: chr3-52407041; COSMIC: COSV70227362; COSMIC: COSV70227362;