rs56002041

Positions:

• chr3-52375405-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015512.5(DNAH1):​c.7151A>G​(p.Asn2384Ser) variant causes a missense change. The variant allele was found at a frequency of 0.109 in 1,612,530 control chromosomes in the GnomAD database, including 10,807 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (616 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10191 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.77

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=0.0019221604).
• BP6: Variant 3-52375405-A-G is Benign according to our data. Variant chr3-52375405-A-G is described in ClinVar as [Benign]. Clinvar id is 402602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.7151A>G	p.Asn2384Ser	missense_variant	45/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.7220A>G	p.Asn2407Ser	missense_variant	47/80		XP_016861618.1
DNAH1	XM_017006130.2	c.7151A>G	p.Asn2384Ser	missense_variant	46/79		XP_016861619.1
DNAH1	XM_017006131.2	c.7220A>G	p.Asn2407Ser	missense_variant	47/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.7151A>G	p.Asn2384Ser	missense_variant	45/78	1	NM_015512.5	ENSP00000401514	P1
DNAH1	ENST00000486752.5	n.7412A>G		non_coding_transcript_exon_variant	45/77	2

Frequencies

GnomAD3 genomes AF: 0.0779 AC: 11851 AN: 152166 Hom.: 617 Cov.: 32

Gnomad AFR AF: 0.0200

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0742

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0660

Gnomad FIN AF: 0.0526

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.102

GnomAD3 exomes AF: 0.0836 AC: 20628 AN: 246688 Hom.: 1040 AF XY: 0.0848 AC XY: 11357 AN XY: 133862

Gnomad AFR exome AF: 0.0179

Gnomad AMR exome AF: 0.0634

Gnomad ASJ exome AF: 0.119

Gnomad EAS exome AF: 0.000279

Gnomad SAS exome AF: 0.0720

Gnomad FIN exome AF: 0.0566

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.0913

GnomAD4 exome AF: 0.112 AC: 163898 AN: 1460246 Hom.: 10191 Cov.: 32 AF XY: 0.111 AC XY: 80613 AN XY: 726340

Gnomad4 AFR exome AF: 0.0188

Gnomad4 AMR exome AF: 0.0663

Gnomad4 ASJ exome AF: 0.120

Gnomad4 EAS exome AF: 0.000328

Gnomad4 SAS exome AF: 0.0751

Gnomad4 FIN exome AF: 0.0593

Gnomad4 NFE exome AF: 0.127

Gnomad4 OTH exome AF: 0.105

GnomAD4 genome AF: 0.0778 AC: 11847 AN: 152284 Hom.: 616 Cov.: 32 AF XY: 0.0751 AC XY: 5592 AN XY: 74474

Gnomad4 AFR AF: 0.0200

Gnomad4 AMR AF: 0.0741

Gnomad4 ASJ AF: 0.126

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0667

Gnomad4 FIN AF: 0.0526

Gnomad4 NFE AF: 0.121

Gnomad4 OTH AF: 0.101

Alfa AF: 0.113 Hom.: 1497

Bravo AF: 0.0763

TwinsUK AF: 0.130 AC: 483

ALSPAC AF: 0.127 AC: 491

ESP6500AA AF: 0.0183 AC: 76

ESP6500EA AF: 0.122 AC: 1026

ExAC AF: 0.0828 AC: 10023

Asia WGS AF: 0.0260 AC: 93 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	13
DANN	Benign	0.67
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.059
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.052
MPC		0.098
ClinPred		0.0017	T
GERP RS		2.9
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs56002041; hg19: chr3-52409421; COSMIC: COSV70229077; COSMIC: COSV70229077;