rs142935638

Positions:

• chr3-52345640-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.1590C>T​(p.His530=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,611,676 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (23 hom.)
• Consequence: DNAH1 NM_015512.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.142

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=-0.52).
• BP6: Variant 3-52345640-C-T is Benign according to our data. Variant chr3-52345640-C-T is described in ClinVar as [Benign]. Clinvar id is 544647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.142 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00125 (190/152340) while in subpopulation SAS AF= 0.0137 (66/4826). AF 95% confidence interval is 0.011. There are 4 homozygotes in gnomad4. There are 125 alleles in male gnomad4 subpopulation. Median coverage is 33. 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.1590C>T	p.His530=	synonymous_variant	10/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.1590C>T	p.His530=	synonymous_variant	11/80		XP_016861618.1
DNAH1	XM_017006130.2	c.1590C>T	p.His530=	synonymous_variant	11/79		XP_016861619.1
DNAH1	XM_017006131.2	c.1590C>T	p.His530=	synonymous_variant	11/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.1590C>T	p.His530=	synonymous_variant	10/78	1	NM_015512.5	ENSP00000401514	P1
DNAH1	ENST00000486752.5	n.1851C>T		non_coding_transcript_exon_variant	10/77	2
DNAH1	ENST00000497875.1	n.1755C>T		non_coding_transcript_exon_variant	11/21	2

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 190 AN: 152222 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000602

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00222 AC: 543 AN: 244486 Hom.: 5 AF XY: 0.00282 AC XY: 374 AN XY: 132652

Gnomad AFR exome AF: 0.000203

Gnomad AMR exome AF: 0.000824

Gnomad ASJ exome AF: 0.00714

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0117

Gnomad FIN exome AF: 0.0000942

Gnomad NFE exome AF: 0.000757

Gnomad OTH exome AF: 0.00100

GnomAD4 exome AF: 0.00118 AC: 1723 AN: 1459336 Hom.: 23 Cov.: 32 AF XY: 0.00154 AC XY: 1114 AN XY: 725690

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000654

Gnomad4 ASJ exome AF: 0.00745

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0115

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.000346

Gnomad4 OTH exome AF: 0.00149

GnomAD4 genome AF: 0.00125 AC: 190 AN: 152340 Hom.: 4 Cov.: 33 AF XY: 0.00168 AC XY: 125 AN XY: 74488

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0137

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.000846

Asia WGS AF: 0.00462 AC: 16 AN: 3478

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	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	DNAH1: BP4, BP7, BS1, BS2 -
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 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	7.3
DANN	Benign	0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs142935638; hg19: chr3-52379656;