rs201113513

chr3-52345604-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM2 BP4_Strong BP6_Moderate BP7 BS1

The NM_015512.5(DNAH1):c.1554C>T(p.Ala518=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000163 in 1,606,050 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00097 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: DNAH1 NM_015512.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.868

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 -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 3-52345604-C-T is Benign according to our data. Variant chr3-52345604-C-T is described in ClinVar as [Benign]. Clinvar id is 544664.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.868 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000965 (147/152270) while in subpopulation AFR AF= 0.00339 (141/41548). AF 95% confidence interval is 0.00294. There are 1 homozygotes in gnomad4. There are 66 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.1554C>T	p.Ala518=	synonymous_variant	10/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.1554C>T	p.Ala518=	synonymous_variant	11/80
DNAH1	XM_017006130.2	c.1554C>T	p.Ala518=	synonymous_variant	11/79
DNAH1	XM_017006131.2	c.1554C>T	p.Ala518=	synonymous_variant	11/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.1554C>T	p.Ala518=	synonymous_variant	10/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.1815C>T		non_coding_transcript_exon_variant	10/77	2
DNAH1	ENST00000497875.1	n.1719C>T		non_coding_transcript_exon_variant	11/21	2

Frequencies

GnomAD3 genomes AF: 0.000933 AC: 142 AN: 152152 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000179 AC: 42 AN: 234668 Hom.: 0 AF XY: 0.0000943 AC XY: 12 AN XY: 127212

Gnomad AFR exome AF: 0.00275

Gnomad AMR exome AF: 0.0000911

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000784 AC: 114 AN: 1453780 Hom.: 0 Cov.: 32 AF XY: 0.0000706 AC XY: 51 AN XY: 722442

Gnomad4 AFR exome AF: 0.00264

Gnomad4 AMR exome AF: 0.0000690

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000632

Gnomad4 OTH exome AF: 0.000250

GnomAD4 genome AF: 0.000965 AC: 147 AN: 152270 Hom.: 1 Cov.: 33 AF XY: 0.000886 AC XY: 66 AN XY: 74462

Gnomad4 AFR AF: 0.00339

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000510 Hom.: 0

Bravo AF: 0.00107

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	5.7
Dann	Benign	0.82

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: rs201113513; hg19: chr3-52379620;