chr3-52392973-T-C

Position:

• chr3-52392973-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015512.5(DNAH1):​c.10422T>C​(p.Leu3474Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00559 in 1,613,646 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0058 (65 hom.)
• Consequence: DNAH1 NM_015512.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.40

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 3-52392973-T-C is Benign according to our data. Variant chr3-52392973-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 478383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.4 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00374 (569/151986) while in subpopulation SAS AF= 0.0231 (111/4800). AF 95% confidence interval is 0.0196. There are 4 homozygotes in gnomad4. There are 287 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.10422T>C	p.Leu3474Leu	synonymous_variant	65/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.10491T>C	p.Leu3497Leu	synonymous_variant	67/80		XP_016861618.1
DNAH1	XM_017006130.2	c.10422T>C	p.Leu3474Leu	synonymous_variant	66/79		XP_016861619.1
DNAH1	XM_017006131.2	c.10365T>C	p.Leu3455Leu	synonymous_variant	66/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.10422T>C	p.Leu3474Leu	synonymous_variant	65/78	1	NM_015512.5	ENSP00000401514.2
DNAH1	ENST00000486752.5	n.10879T>C		non_coding_transcript_exon_variant	64/77	2
DNAH1	ENST00000488988.5	n.2208T>C		non_coding_transcript_exon_variant	12/25	2
DNAH1	ENST00000490713.5	n.1122T>C		non_coding_transcript_exon_variant	8/20	5		ENSP00000419071.1

Frequencies

GnomAD3 genomes AF: 0.00375 AC: 570 AN: 151868 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.000920

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00424

Gnomad SAS AF: 0.0233

Gnomad FIN AF: 0.00142

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00475

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00567 AC: 1412 AN: 249216 Hom.: 10 AF XY: 0.00670 AC XY: 906 AN XY: 135188

Gnomad AFR exome AF: 0.000904

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00367

Gnomad SAS exome AF: 0.0232

Gnomad FIN exome AF: 0.00158

Gnomad NFE exome AF: 0.00418

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00579 AC: 8458 AN: 1461660 Hom.: 65 Cov.: 38 AF XY: 0.00632 AC XY: 4598 AN XY: 727108

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.00380

Gnomad4 SAS exome AF: 0.0233

Gnomad4 FIN exome AF: 0.00152

Gnomad4 NFE exome AF: 0.00511

Gnomad4 OTH exome AF: 0.00571

GnomAD4 genome AF: 0.00374 AC: 569 AN: 151986 Hom.: 4 Cov.: 31 AF XY: 0.00386 AC XY: 287 AN XY: 74280

Gnomad4 AFR AF: 0.000917

Gnomad4 AMR AF: 0.00308

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00425

Gnomad4 SAS AF: 0.0231

Gnomad4 FIN AF: 0.00142

Gnomad4 NFE AF: 0.00474

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00396 Hom.: 6

Bravo AF: 0.00292

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.00403

EpiControl AF: 0.00504

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 25, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	3.0
DANN	Benign	0.71

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: rs148913561; hg19: chr3-52426989;