rs80128076

Positions:

• chr3-52368828-G-A

Variant summary

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

The ENST00000420323.7(DNAH1):​c.5853G>A​(p.Val1951=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00431 in 1,614,008 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (30 hom.)
• Consequence: DNAH1 ENST00000420323.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.154

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 3-52368828-G-A is Benign according to our data. Variant chr3-52368828-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 478468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.154 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00333 (507/152308) while in subpopulation SAS AF= 0.00643 (31/4824). AF 95% confidence interval is 0.00465. There are 2 homozygotes in gnomad4. There are 252 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.5853G>A	p.Val1951=	synonymous_variant	37/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.5922G>A	p.Val1974=	synonymous_variant	39/80		XP_016861618.1
DNAH1	XM_017006130.2	c.5853G>A	p.Val1951=	synonymous_variant	38/79		XP_016861619.1
DNAH1	XM_017006131.2	c.5922G>A	p.Val1974=	synonymous_variant	39/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.5853G>A	p.Val1951=	synonymous_variant	37/78	1	NM_015512.5	ENSP00000401514	P1
DNAH1	ENST00000486752.5	n.6114G>A		non_coding_transcript_exon_variant	37/77	2

Frequencies

GnomAD3 genomes AF: 0.00333 AC: 507 AN: 152190 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00478

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00386 AC: 963 AN: 249268 Hom.: 3 AF XY: 0.00419 AC XY: 567 AN XY: 135224

Gnomad AFR exome AF: 0.000710

Gnomad AMR exome AF: 0.00293

Gnomad ASJ exome AF: 0.00447

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00791

Gnomad FIN exome AF: 0.00144

Gnomad NFE exome AF: 0.00443

Gnomad OTH exome AF: 0.00528

GnomAD4 exome AF: 0.00442 AC: 6456 AN: 1461700 Hom.: 30 Cov.: 31 AF XY: 0.00455 AC XY: 3309 AN XY: 727132

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00250

Gnomad4 ASJ exome AF: 0.00494

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00793

Gnomad4 FIN exome AF: 0.00182

Gnomad4 NFE exome AF: 0.00458

Gnomad4 OTH exome AF: 0.00462

GnomAD4 genome AF: 0.00333 AC: 507 AN: 152308 Hom.: 2 Cov.: 32 AF XY: 0.00338 AC XY: 252 AN XY: 74468

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00643

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00478

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00390 Hom.: 0

Bravo AF: 0.00297

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00513

EpiControl AF: 0.00462

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	DNAH1: BP4, BP7, BS2 -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	7.1
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs80128076; hg19: chr3-52402844;