3-52380096-C-T

Position:

• chr3-52380096-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.7569C>T​(p.Ser2523=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 1,604,444 control chromosomes in the GnomAD database, including 378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (25 hom., cov: 32)
  • Exomes 𝑓: 0.020 (353 hom.)
• Consequence: DNAH1 NM_015512.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.722

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=-0.63).
• BP6: Variant 3-52380096-C-T is Benign according to our data. Variant chr3-52380096-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 478493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-52380096-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.722 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0159 (2420/152248) while in subpopulation AMR AF= 0.0235 (359/15302). AF 95% confidence interval is 0.0219. There are 25 homozygotes in gnomad4. There are 1153 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.7569C>T	p.Ser2523=	synonymous_variant	48/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.7638C>T	p.Ser2546=	synonymous_variant	50/80		XP_016861618.1
DNAH1	XM_017006130.2	c.7569C>T	p.Ser2523=	synonymous_variant	49/79		XP_016861619.1
DNAH1	XM_017006131.2	c.7638C>T	p.Ser2546=	synonymous_variant	50/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.7569C>T	p.Ser2523=	synonymous_variant	48/78	1	NM_015512.5	ENSP00000401514	P1
DNAH1	ENST00000486752.5	n.7830C>T		non_coding_transcript_exon_variant	48/77	2

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2419 AN: 152130 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00374

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0235

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0237

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0228

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.0156 AC: 3625 AN: 231986 Hom.: 49 AF XY: 0.0157 AC XY: 1978 AN XY: 125602

Gnomad AFR exome AF: 0.00310

Gnomad AMR exome AF: 0.0181

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00103

Gnomad FIN exome AF: 0.0218

Gnomad NFE exome AF: 0.0220

Gnomad OTH exome AF: 0.0192

GnomAD4 exome AF: 0.0200 AC: 29024 AN: 1452196 Hom.: 353 Cov.: 31 AF XY: 0.0196 AC XY: 14113 AN XY: 721416

Gnomad4 AFR exome AF: 0.00429

Gnomad4 AMR exome AF: 0.0184

Gnomad4 ASJ exome AF: 0.0112

Gnomad4 EAS exome AF: 0.0000509

Gnomad4 SAS exome AF: 0.00150

Gnomad4 FIN exome AF: 0.0212

Gnomad4 NFE exome AF: 0.0229

Gnomad4 OTH exome AF: 0.0181

GnomAD4 genome AF: 0.0159 AC: 2420 AN: 152248 Hom.: 25 Cov.: 32 AF XY: 0.0155 AC XY: 1153 AN XY: 74454

Gnomad4 AFR AF: 0.00375

Gnomad4 AMR AF: 0.0235

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.0237

Gnomad4 NFE AF: 0.0228

Gnomad4 OTH AF: 0.0242

Alfa AF: 0.0191 Hom.: 16

Bravo AF: 0.0161

Asia WGS AF: 0.00202 AC: 8 AN: 3478

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	Nov 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 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 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	2.3
DANN	Benign	0.58

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: rs73072968; hg19: chr3-52414112;