chr3-52360012-G-A

Position:

• chr3-52360012-G-A

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.4504G>A​(p.Val1502Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00468 in 1,613,944 control chromosomes in the GnomAD database, including 275 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (142 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (133 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 8.14

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=0.004504442).
• BP6: Variant 3-52360012-G-A is Benign according to our data. Variant chr3-52360012-G-A is described in ClinVar as [Benign]. Clinvar id is 478448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0779 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.4504G>A	p.Val1502Met	missense_variant	27/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.4504G>A	p.Val1502Met	missense_variant	28/80
DNAH1	XM_017006130.2	c.4504G>A	p.Val1502Met	missense_variant	28/79
DNAH1	XM_017006131.2	c.4504G>A	p.Val1502Met	missense_variant	28/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.4504G>A	p.Val1502Met	missense_variant	27/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.4765G>A		non_coding_transcript_exon_variant	27/77	2

Frequencies

GnomAD3 genomes AF: 0.0235 AC: 3570 AN: 152238 Hom.: 143 Cov.: 33

Gnomad AFR AF: 0.0804

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00949

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.00611 AC: 1523 AN: 249102 Hom.: 45 AF XY: 0.00483 AC XY: 653 AN XY: 135110

Gnomad AFR exome AF: 0.0788

Gnomad AMR exome AF: 0.00594

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000523

Gnomad OTH exome AF: 0.00330

GnomAD4 exome AF: 0.00273 AC: 3986 AN: 1461588 Hom.: 133 Cov.: 31 AF XY: 0.00241 AC XY: 1749 AN XY: 727074

Gnomad4 AFR exome AF: 0.0818

Gnomad4 AMR exome AF: 0.00642

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000425

Gnomad4 OTH exome AF: 0.00671

GnomAD4 genome AF: 0.0235 AC: 3574 AN: 152356 Hom.: 142 Cov.: 33 AF XY: 0.0223 AC XY: 1663 AN XY: 74506

Gnomad4 AFR AF: 0.0802

Gnomad4 AMR AF: 0.00947

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.00417 Hom.: 34

Bravo AF: 0.0264

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0721 AC: 311

ESP6500EA AF: 0.000587 AC: 5

ExAC AF: 0.00733 AC: 888

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000652

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 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	Sep 21, 2023	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	30
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.52	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Vest4		0.83
MVP		0.60
MPC		0.58
ClinPred		0.073	T
GERP RS		5.1
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs17052095; hg19: chr3-52394028;