rs61731638

Positions:

• chr3-52388284-C-T

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.9121C>T​(p.Arg3041Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00358 in 1,601,154 control chromosomes in the GnomAD database, including 174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3041H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.018 (74 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (100 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.99

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=0.010356903).
• BP6: Variant 3-52388284-C-T is Benign according to our data. Variant chr3-52388284-C-T is described in ClinVar as [Benign]. Clinvar id is 478508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0612 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.9121C>T	p.Arg3041Cys	missense_variant	57/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.9190C>T	p.Arg3064Cys	missense_variant	59/80
DNAH1	XM_017006130.2	c.9121C>T	p.Arg3041Cys	missense_variant	58/79
DNAH1	XM_017006131.2	c.9190C>T	p.Arg3064Cys	missense_variant	59/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.9121C>T	p.Arg3041Cys	missense_variant	57/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.9382C>T		non_coding_transcript_exon_variant	57/77	2
DNAH1	ENST00000488988.5	n.711C>T		non_coding_transcript_exon_variant	5/25	2

Frequencies

GnomAD3 genomes AF: 0.0184 AC: 2794 AN: 152218 Hom.: 74 Cov.: 33

Gnomad AFR AF: 0.0633

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00857

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00460 AC: 1038 AN: 225496 Hom.: 31 AF XY: 0.00370 AC XY: 452 AN XY: 122062

Gnomad AFR exome AF: 0.0682

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000145

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000266

Gnomad OTH exome AF: 0.00176

GnomAD4 exome AF: 0.00202 AC: 2933 AN: 1448818 Hom.: 100 Cov.: 32 AF XY: 0.00177 AC XY: 1270 AN XY: 719336

Gnomad4 AFR exome AF: 0.0703

Gnomad4 AMR exome AF: 0.00381

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000107

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000135

Gnomad4 OTH exome AF: 0.00439

GnomAD4 genome AF: 0.0184 AC: 2798 AN: 152336 Hom.: 74 Cov.: 33 AF XY: 0.0178 AC XY: 1327 AN XY: 74492

Gnomad4 AFR AF: 0.0632

Gnomad4 AMR AF: 0.00856

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.00466 Hom.: 22

Bravo AF: 0.0219

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0529 AC: 223

ESP6500EA AF: 0.000236 AC: 2

ExAC AF: 0.00526 AC: 637

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 31213628) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 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	0.31
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	27
DANN	Pathogenic	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.45	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Vest4		0.79
MVP		0.64
MPC		0.67
ClinPred		0.041	T
GERP RS		4.3
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61731638; hg19: chr3-52422300;