chr3-52353276-C-T

Position:

• chr3-52353276-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.3201C>T​(p.Cys1067=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00955 in 1,613,862 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0098 (105 hom.)
• Consequence: DNAH1 NM_015512.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.19

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=-0.53).
• BP6: Variant 3-52353276-C-T is Benign according to our data. Variant chr3-52353276-C-T is described in ClinVar as [Benign]. Clinvar id is 478439.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.19 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00719 (1095/152316) while in subpopulation NFE AF= 0.0114 (779/68036). AF 95% confidence interval is 0.0108. There are 7 homozygotes in gnomad4. There are 546 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.3201C>T	p.Cys1067=	synonymous_variant	19/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.3201C>T	p.Cys1067=	synonymous_variant	20/80		XP_016861618.1
DNAH1	XM_017006130.2	c.3201C>T	p.Cys1067=	synonymous_variant	20/79		XP_016861619.1
DNAH1	XM_017006131.2	c.3201C>T	p.Cys1067=	synonymous_variant	20/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.3201C>T	p.Cys1067=	synonymous_variant	19/78	1	NM_015512.5	ENSP00000401514	P1
DNAH1	ENST00000486752.5	n.3462C>T		non_coding_transcript_exon_variant	19/77	2
DNAH1	ENST00000497875.1	n.3366C>T		non_coding_transcript_exon_variant	20/21	2

Frequencies

GnomAD3 genomes AF: 0.00720 AC: 1096 AN: 152198 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00866 AC: 2153 AN: 248712 Hom.: 19 AF XY: 0.00882 AC XY: 1190 AN XY: 134904

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0177

Gnomad NFE exome AF: 0.0144

Gnomad OTH exome AF: 0.00844

GnomAD4 exome AF: 0.00980 AC: 14324 AN: 1461546 Hom.: 105 Cov.: 31 AF XY: 0.00952 AC XY: 6924 AN XY: 727054

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.00210

Gnomad4 ASJ exome AF: 0.00130

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0196

Gnomad4 NFE exome AF: 0.0113

Gnomad4 OTH exome AF: 0.00802

GnomAD4 genome AF: 0.00719 AC: 1095 AN: 152316 Hom.: 7 Cov.: 33 AF XY: 0.00733 AC XY: 546 AN XY: 74482

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.00444

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0148

Gnomad4 NFE AF: 0.0114

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00869 Hom.: 0

Bravo AF: 0.00563

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00872

EpiControl AF: 0.0104

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.53
DANN	Benign	0.59

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: rs114066123; hg19: chr3-52387292;