rs75513160

Positions:

• chr3-52392856-G-A

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.10305G>A​(p.Thr3435=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0031 in 1,597,196 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (64 hom., cov: 29)
  • Exomes 𝑓: 0.0019 (66 hom.)
• Consequence: DNAH1 NM_015512.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.32

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=-0.43).
• BP6: Variant 3-52392856-G-A is Benign according to our data. Variant chr3-52392856-G-A is described in ClinVar as [Benign]. Clinvar id is 478377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.32 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.10305G>A	p.Thr3435=	synonymous_variant	65/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.10374G>A	p.Thr3458=	synonymous_variant	67/80
DNAH1	XM_017006130.2	c.10305G>A	p.Thr3435=	synonymous_variant	66/79
DNAH1	XM_017006131.2	c.10248G>A	p.Thr3416=	synonymous_variant	66/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.10305G>A	p.Thr3435=	synonymous_variant	65/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.10762G>A		non_coding_transcript_exon_variant	64/77	2
DNAH1	ENST00000488988.5	n.2091G>A		non_coding_transcript_exon_variant	12/25	2
DNAH1	ENST00000490713.5	c.1005G>A	p.Thr335=	synonymous_variant, NMD_transcript_variant	8/20	5

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2205 AN: 143144 Hom.: 64 Cov.: 29

Gnomad AFR AF: 0.0544

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000439

Gnomad FIN AF: 0.000226

Gnomad MID AF: 0.00680

Gnomad NFE AF: 0.000703

Gnomad OTH AF: 0.0107

GnomAD3 exomes AF: 0.00391 AC: 969 AN: 247530 Hom.: 30 AF XY: 0.00282 AC XY: 379 AN XY: 134388

Gnomad AFR exome AF: 0.0530

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000655

Gnomad OTH exome AF: 0.00282

GnomAD4 exome AF: 0.00189 AC: 2742 AN: 1453972 Hom.: 66 Cov.: 39 AF XY: 0.00165 AC XY: 1190 AN XY: 721488

Gnomad4 AFR exome AF: 0.0564

Gnomad4 AMR exome AF: 0.00202

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000256

Gnomad4 FIN exome AF: 0.000320

Gnomad4 NFE exome AF: 0.000427

Gnomad4 OTH exome AF: 0.00390

GnomAD4 genome AF: 0.0154 AC: 2211 AN: 143224 Hom.: 64 Cov.: 29 AF XY: 0.0148 AC XY: 1021 AN XY: 68876

Gnomad4 AFR AF: 0.0544

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000441

Gnomad4 FIN AF: 0.000226

Gnomad4 NFE AF: 0.000703

Gnomad4 OTH AF: 0.0106

Alfa AF: 0.00622 Hom.: 10

Bravo AF: 0.0175

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2020	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	4.8
DANN	Benign	0.72

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: rs75513160; hg19: chr3-52426872;