rs61734643

Positions:

• chr3-52351976-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015512.5(DNAH1):​c.2744A>G​(p.Asn915Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00556 in 1,602,576 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (65 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.489

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=0.007988453).
• BP6: Variant 3-52351976-A-G is Benign according to our data. Variant chr3-52351976-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 478434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00375 (571/152342) while in subpopulation SAS AF= 0.0232 (112/4828). AF 95% confidence interval is 0.0197. There are 4 homozygotes in gnomad4. There are 290 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.2744A>G	p.Asn915Ser	missense_variant	17/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.2744A>G	p.Asn915Ser	missense_variant	18/80
DNAH1	XM_017006130.2	c.2744A>G	p.Asn915Ser	missense_variant	18/79
DNAH1	XM_017006131.2	c.2744A>G	p.Asn915Ser	missense_variant	18/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.2744A>G	p.Asn915Ser	missense_variant	17/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.3005A>G		non_coding_transcript_exon_variant	17/77	2
DNAH1	ENST00000497875.1	n.2909A>G		non_coding_transcript_exon_variant	18/21	2

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 572 AN: 152224 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00443

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00475

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00555 AC: 1283 AN: 231132 Hom.: 11 AF XY: 0.00655 AC XY: 818 AN XY: 124886

Gnomad AFR exome AF: 0.000888

Gnomad AMR exome AF: 0.00245

Gnomad ASJ exome AF: 0.00166

Gnomad EAS exome AF: 0.00349

Gnomad SAS exome AF: 0.0234

Gnomad FIN exome AF: 0.00155

Gnomad NFE exome AF: 0.00403

Gnomad OTH exome AF: 0.00297

GnomAD4 exome AF: 0.00575 AC: 8342 AN: 1450234 Hom.: 65 Cov.: 31 AF XY: 0.00627 AC XY: 4513 AN XY: 720002

Gnomad4 AFR exome AF: 0.000663

Gnomad4 AMR exome AF: 0.00227

Gnomad4 ASJ exome AF: 0.00162

Gnomad4 EAS exome AF: 0.00372

Gnomad4 SAS exome AF: 0.0233

Gnomad4 FIN exome AF: 0.00152

Gnomad4 NFE exome AF: 0.00509

Gnomad4 OTH exome AF: 0.00565

GnomAD4 genome AF: 0.00375 AC: 571 AN: 152342 Hom.: 4 Cov.: 32 AF XY: 0.00389 AC XY: 290 AN XY: 74490

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00444

Gnomad4 SAS AF: 0.0232

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00473

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00397 Hom.: 6

Bravo AF: 0.00291

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000750 AC: 3

ESP6500EA AF: 0.00371 AC: 31

ExAC AF: 0.00564 AC: 681

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 25, 2023	- -

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
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	16
DANN	Benign	0.95
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	0.94	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.082
Sift	Benign	0.49	T
Sift4G	Benign	0.42	T
Vest4		0.19
MVP		0.19
MPC		0.098
ClinPred		0.0058	T
GERP RS		4.4
gMVP		0.40

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: rs61734643; hg19: chr3-52385992;