rs145673040

Positions:

• chr3-52370162-A-G
• chr3-52370162-A-T

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.6191A>G​(p.Asn2064Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,613,844 control chromosomes in the GnomAD database, including 172 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (14 hom., cov: 33)
  • Exomes 𝑓: 0.011 (158 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 8.06

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=0.003696978).
• BP6: Variant 3-52370162-A-G is Benign according to our data. Variant chr3-52370162-A-G is described in ClinVar as [Benign]. Clinvar id is 478474.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 = 0.00941 (1432/152190) while in subpopulation NFE AF= 0.00969 (659/67988). AF 95% confidence interval is 0.00908. There are 14 homozygotes in gnomad4. There are 826 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.6191A>G	p.Asn2064Ser	missense_variant	39/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.6260A>G	p.Asn2087Ser	missense_variant	41/80
DNAH1	XM_017006130.2	c.6191A>G	p.Asn2064Ser	missense_variant	40/79
DNAH1	XM_017006131.2	c.6260A>G	p.Asn2087Ser	missense_variant	41/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.6191A>G	p.Asn2064Ser	missense_variant	39/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.6452A>G		non_coding_transcript_exon_variant	39/77	2

Frequencies

GnomAD3 genomes AF: 0.00941 AC: 1431 AN: 152072 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0536

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00969

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.0106 AC: 2640 AN: 249192 Hom.: 42 AF XY: 0.0110 AC XY: 1488 AN XY: 135206

Gnomad AFR exome AF: 0.00174

Gnomad AMR exome AF: 0.00287

Gnomad ASJ exome AF: 0.00626

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00644

Gnomad FIN exome AF: 0.0507

Gnomad NFE exome AF: 0.00963

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.0107 AC: 15670 AN: 1461654 Hom.: 158 Cov.: 32 AF XY: 0.0106 AC XY: 7702 AN XY: 727108

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.00315

Gnomad4 ASJ exome AF: 0.00704

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00674

Gnomad4 FIN exome AF: 0.0479

Gnomad4 NFE exome AF: 0.0103

Gnomad4 OTH exome AF: 0.0110

GnomAD4 genome AF: 0.00941 AC: 1432 AN: 152190 Hom.: 14 Cov.: 33 AF XY: 0.0111 AC XY: 826 AN XY: 74420

Gnomad4 AFR AF: 0.00178

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.00866

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.0536

Gnomad4 NFE AF: 0.00969

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00864 Hom.: 10

Bravo AF: 0.00618

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00231 AC: 10

ESP6500EA AF: 0.00914 AC: 78

ExAC AF: 0.0100 AC: 1214

Asia WGS AF: 0.00346 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	DNAH1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 03, 2023	- -

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	0.089
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Benign	-0.021
Eigen_PC	Benign	0.061
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.87	D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.12
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.047	D
Vest4		0.43
MPC		0.12
ClinPred		0.032	T
GERP RS		4.5
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs145673040; hg19: chr3-52404178; COSMIC: COSV70235638; COSMIC: COSV70235638;