3-52369869-A-C

Position:

• chr3-52369869-A-C

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.5988A>C​(p.Ser1996=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,613,024 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (33 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (52 hom.)
• Consequence: DNAH1 ENST00000420323.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.26

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=-0.95).
• BP6: Variant 3-52369869-A-C is Benign according to our data. Variant chr3-52369869-A-C is described in ClinVar as [Benign]. Clinvar id is 478471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.26 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0127 (1938/152300) while in subpopulation AFR AF= 0.0435 (1809/41556). AF 95% confidence interval is 0.0419. There are 33 homozygotes in gnomad4. There are 919 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.5988A>C	p.Ser1996=	synonymous_variant	38/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.6057A>C	p.Ser2019=	synonymous_variant	40/80		XP_016861618.1
DNAH1	XM_017006130.2	c.5988A>C	p.Ser1996=	synonymous_variant	39/79		XP_016861619.1
DNAH1	XM_017006131.2	c.6057A>C	p.Ser2019=	synonymous_variant	40/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.5988A>C	p.Ser1996=	synonymous_variant	38/78	1	NM_015512.5	ENSP00000401514	P1
DNAH1	ENST00000486752.5	n.6249A>C		non_coding_transcript_exon_variant	38/77	2

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1937 AN: 152182 Hom.: 33 Cov.: 33

Gnomad AFR AF: 0.0436

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00343 AC: 852 AN: 248676 Hom.: 19 AF XY: 0.00288 AC XY: 388 AN XY: 134882

Gnomad AFR exome AF: 0.0472

Gnomad AMR exome AF: 0.00229

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000267

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00143 AC: 2083 AN: 1460724 Hom.: 52 Cov.: 31 AF XY: 0.00130 AC XY: 947 AN XY: 726480

Gnomad4 AFR exome AF: 0.0479

Gnomad4 AMR exome AF: 0.00289

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000130

Gnomad4 OTH exome AF: 0.00315

GnomAD4 genome AF: 0.0127 AC: 1938 AN: 152300 Hom.: 33 Cov.: 33 AF XY: 0.0123 AC XY: 919 AN XY: 74472

Gnomad4 AFR AF: 0.0435

Gnomad4 AMR AF: 0.00627

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00677 Hom.: 8

Bravo AF: 0.0154

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000296

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	Jan 31, 2022	- -
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 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.12
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61753436; hg19: chr3-52403885;