rs201299120

chr3-52375988-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_015512.5(DNAH1):c.7193G>A(p.Arg2398His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00376 in 1,611,914 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2398C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (17 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.01

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 -16 ACMG points.

• BP6: Variant 3-52375988-G-A is Benign according to our data. Variant chr3-52375988-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 478488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00236 (360/152244) while in subpopulation NFE AF= 0.0036 (245/68008). AF 95% confidence interval is 0.00323. There are 4 homozygotes in gnomad4. There are 162 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.7193G>A	p.Arg2398His	missense_variant	46/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.7262G>A	p.Arg2421His	missense_variant	48/80
DNAH1	XM_017006130.2	c.7193G>A	p.Arg2398His	missense_variant	47/79
DNAH1	XM_017006131.2	c.7262G>A	p.Arg2421His	missense_variant	48/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.7193G>A	p.Arg2398His	missense_variant	46/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.7454G>A		non_coding_transcript_exon_variant	46/77	2

Frequencies

GnomAD3 genomes AF: 0.00236 AC: 359 AN: 152126 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.0429

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00360

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00207 AC: 511 AN: 246984 Hom.: 2 AF XY: 0.00218 AC XY: 293 AN XY: 134162

Gnomad AFR exome AF: 0.000779

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.000113

Gnomad SAS exome AF: 0.00165

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00342

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.00390 AC: 5694 AN: 1459670 Hom.: 17 Cov.: 31 AF XY: 0.00382 AC XY: 2773 AN XY: 726176

Gnomad4 AFR exome AF: 0.000660

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00147

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00468

Gnomad4 OTH exome AF: 0.00431

GnomAD4 genome AF: 0.00236 AC: 360 AN: 152244 Hom.: 4 Cov.: 32 AF XY: 0.00218 AC XY: 162 AN XY: 74434

Gnomad4 AFR AF: 0.000843

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00360

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00315 Hom.: 3

Bravo AF: 0.00255

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000507 AC: 2

ESP6500EA AF: 0.00410 AC: 34

ExAC AF: 0.00183 AC: 221

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00338

EpiControl AF: 0.00416

ClinVar

Significance: 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	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	DNAH1: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
Cadd	Uncertain	26
Dann	Uncertain	1.0
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.054
Sift	Benign	0.098	T
Sift4G	Benign	0.066	T
Vest4		0.37
MVP		0.24
MPC		0.16
ClinPred		0.021	T
GERP RS		4.5
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201299120; hg19: chr3-52410004; COSMIC: COSV101327390; COSMIC: COSV101327390;