rs61734654

Positions:

• chr3-52346604-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015512.5(DNAH1):​c.1789C>T​(p.Arg597Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,614,044 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R597H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (64 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (47 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.19

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004741758).
• BP6: Variant 3-52346604-C-T is Benign according to our data. Variant chr3-52346604-C-T is described in ClinVar as [Benign]. Clinvar id is 478417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.1789C>T	p.Arg597Cys	missense_variant	11/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.1789C>T	p.Arg597Cys	missense_variant	12/80
DNAH1	XM_017006130.2	c.1789C>T	p.Arg597Cys	missense_variant	12/79
DNAH1	XM_017006131.2	c.1789C>T	p.Arg597Cys	missense_variant	12/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.1789C>T	p.Arg597Cys	missense_variant	11/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.2050C>T		non_coding_transcript_exon_variant	11/77	2
DNAH1	ENST00000497875.1	n.1954C>T		non_coding_transcript_exon_variant	12/21	2

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2244 AN: 152222 Hom.: 64 Cov.: 33

Gnomad AFR AF: 0.0522

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00352 AC: 878 AN: 249252 Hom.: 20 AF XY: 0.00260 AC XY: 352 AN XY: 135216

Gnomad AFR exome AF: 0.0521

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000708

Gnomad OTH exome AF: 0.000991

GnomAD4 exome AF: 0.00143 AC: 2094 AN: 1461704 Hom.: 47 Cov.: 32 AF XY: 0.00117 AC XY: 848 AN XY: 727132

Gnomad4 AFR exome AF: 0.0537

Gnomad4 AMR exome AF: 0.00192

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000342

Gnomad4 OTH exome AF: 0.00248

GnomAD4 genome AF: 0.0148 AC: 2250 AN: 152340 Hom.: 64 Cov.: 33 AF XY: 0.0142 AC XY: 1061 AN XY: 74494

Gnomad4 AFR AF: 0.0522

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00257 Hom.: 11

Bravo AF: 0.0166

ESP6500AA AF: 0.0501 AC: 216

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00460 AC: 557

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

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	Aug 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2020	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	-0.011
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Benign	0.086
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.041	D
Vest4		0.33
MVP		0.24
MPC		0.18
ClinPred		0.048	T
GERP RS		4.4
gMVP		0.36

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: rs61734654; hg19: chr3-52380620; COSMIC: COSV70227975;