rs199505182

Positions:

• chr3-52331209-C-T

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.933C>T​(p.Asp311Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00528 in 1,609,148 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (28 hom.)
• Consequence: DNAH1 NM_015512.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.470

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=-0.77).
• BP6: Variant 3-52331209-C-T is Benign according to our data. Variant chr3-52331209-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 478510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00396 (603/152264) while in subpopulation AMR AF= 0.00667 (102/15302). AF 95% confidence interval is 0.00562. There are 2 homozygotes in gnomad4. There are 276 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.933C>T	p.Asp311Asp	synonymous_variant	7/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.933C>T	p.Asp311Asp	synonymous_variant	8/80		XP_016861618.1
DNAH1	XM_017006130.2	c.933C>T	p.Asp311Asp	synonymous_variant	8/79		XP_016861619.1
DNAH1	XM_017006131.2	c.933C>T	p.Asp311Asp	synonymous_variant	8/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.933C>T	p.Asp311Asp	synonymous_variant	7/78	1	NM_015512.5	ENSP00000401514.2
DNAH1	ENST00000486752.5	n.1194C>T		non_coding_transcript_exon_variant	7/77	2
DNAH1	ENST00000497875.1	n.1098C>T		non_coding_transcript_exon_variant	8/21	2

Frequencies

GnomAD3 genomes AF: 0.00396 AC: 603 AN: 152146 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.00667

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00610

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00343 AC: 823 AN: 239722 Hom.: 0 AF XY: 0.00345 AC XY: 448 AN XY: 129978

Gnomad AFR exome AF: 0.000835

Gnomad AMR exome AF: 0.00408

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000227

Gnomad SAS exome AF: 0.000584

Gnomad FIN exome AF: 0.000673

Gnomad NFE exome AF: 0.00565

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00541 AC: 7886 AN: 1456884 Hom.: 28 Cov.: 31 AF XY: 0.00533 AC XY: 3857 AN XY: 724086

Gnomad4 AFR exome AF: 0.000688

Gnomad4 AMR exome AF: 0.00400

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000553

Gnomad4 FIN exome AF: 0.000696

Gnomad4 NFE exome AF: 0.00656

Gnomad4 OTH exome AF: 0.00511

GnomAD4 genome AF: 0.00396 AC: 603 AN: 152264 Hom.: 2 Cov.: 32 AF XY: 0.00371 AC XY: 276 AN XY: 74458

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00667

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00610

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00511 Hom.: 2

Bravo AF: 0.00426

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 28, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	DNAH1: BP4, BP7 -

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	-0.77
CADD	Benign	3.1
DANN	Benign	0.42

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: rs199505182; hg19: chr3-52365225;