rs61729450

Positions:

• chr3-52326302-T-C

Variant summary

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

The ENST00000420323.7(DNAH1):​c.569T>C​(p.Ile190Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00571 in 1,607,330 control chromosomes in the GnomAD database, including 71 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (66 hom.)
• Consequence: DNAH1 ENST00000420323.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072398186).
• BP6: Variant 3-52326302-T-C is Benign according to our data. Variant chr3-52326302-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 478464.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 = 0.00393 (599/152238) while in subpopulation SAS AF= 0.0232 (112/4822). AF 95% confidence interval is 0.0197. There are 5 homozygotes in gnomad4. There are 303 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.569T>C	p.Ile190Thr	missense_variant	4/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.569T>C	p.Ile190Thr	missense_variant	5/80		XP_016861618.1
DNAH1	XM_017006130.2	c.569T>C	p.Ile190Thr	missense_variant	5/79		XP_016861619.1
DNAH1	XM_017006131.2	c.569T>C	p.Ile190Thr	missense_variant	5/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.569T>C	p.Ile190Thr	missense_variant	4/78	1	NM_015512.5	ENSP00000401514	P1
DNAH1	ENST00000486752.5	n.830T>C		non_coding_transcript_exon_variant	4/77	2
DNAH1	ENST00000497875.1	n.734T>C		non_coding_transcript_exon_variant	5/21	2

Frequencies

GnomAD3 genomes AF: 0.00394 AC: 600 AN: 152120 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00905

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00479

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00600 AC: 1455 AN: 242462 Hom.: 10 AF XY: 0.00703 AC XY: 929 AN XY: 132060

Gnomad AFR exome AF: 0.000783

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.00687

Gnomad SAS exome AF: 0.0231

Gnomad FIN exome AF: 0.00163

Gnomad NFE exome AF: 0.00421

Gnomad OTH exome AF: 0.00301

GnomAD4 exome AF: 0.00590 AC: 8580 AN: 1455092 Hom.: 66 Cov.: 31 AF XY: 0.00643 AC XY: 4655 AN XY: 724066

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.00713

Gnomad4 SAS exome AF: 0.0233

Gnomad4 FIN exome AF: 0.00153

Gnomad4 NFE exome AF: 0.00511

Gnomad4 OTH exome AF: 0.00570

GnomAD4 genome AF: 0.00393 AC: 599 AN: 152238 Hom.: 5 Cov.: 32 AF XY: 0.00407 AC XY: 303 AN XY: 74438

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00907

Gnomad4 SAS AF: 0.0232

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00478

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00421 Hom.: 7

Bravo AF: 0.00315

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000967 AC: 4

ESP6500EA AF: 0.00381 AC: 32

ExAC AF: 0.00632 AC: 765

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.00403

EpiControl AF: 0.00510

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 25, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 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 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Uncertain	0.98
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.089
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.85	D
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.063
Sift	Benign	0.059	T
Sift4G	Uncertain	0.0050	D
Vest4		0.31
MVP		0.41
MPC		0.16
ClinPred		0.015	T
GERP RS		2.3
gMVP		0.53

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: rs61729450; hg19: chr3-52360318;