rs200859252

chr3-52366791-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_015512.5(DNAH1):c.5669G>T(p.Gly1890Val) variant causes a missense change. The variant allele was found at a frequency of 0.00156 in 1,613,910 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (6 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 6.68

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011011511).
• BP6: Variant 3-52366791-G-T is Benign according to our data. Variant chr3-52366791-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 478462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.5669G>T	p.Gly1890Val	missense_variant	36/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.5669G>T	p.Gly1890Val	missense_variant	37/80
DNAH1	XM_017006130.2	c.5669G>T	p.Gly1890Val	missense_variant	37/79
DNAH1	XM_017006131.2	c.5669G>T	p.Gly1890Val	missense_variant	37/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.5669G>T	p.Gly1890Val	missense_variant	36/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.5930G>T		non_coding_transcript_exon_variant	36/77	2

Frequencies

GnomAD3 genomes AF: 0.00186 AC: 283 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0117

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00204

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00215 AC: 535 AN: 249130 Hom.: 0 AF XY: 0.00202 AC XY: 273 AN XY: 135134

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.00204

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00153 AC: 2235 AN: 1461634 Hom.: 6 Cov.: 34 AF XY: 0.00152 AC XY: 1102 AN XY: 727112

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0130

Gnomad4 NFE exome AF: 0.00125

Gnomad4 OTH exome AF: 0.00146

GnomAD4 genome AF: 0.00186 AC: 283 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.00214 AC XY: 159 AN XY: 74472

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0117

Gnomad4 NFE AF: 0.00204

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00172 Hom.: 0

Bravo AF: 0.000850

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00118 AC: 10

ExAC AF: 0.00211 AC: 255

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000948

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 23, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 16, 2022

- -

DNAH1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 01, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.030
Cadd	Uncertain	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.55	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.019	D
Vest4		0.74
MVP		0.59
MPC		0.62
ClinPred		0.11	T
GERP RS		5.0
gMVP		0.73

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: rs200859252; hg19: chr3-52400807;