3-52332352-A-G

Position:

• chr3-52332352-A-G

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.1244A>G​(p.Lys415Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00568 in 1,613,982 control chromosomes in the GnomAD database, including 71 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (66 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.68

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047029853).
• BP6: Variant 3-52332352-A-G is Benign according to our data. Variant chr3-52332352-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 478409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0039 (594/152362) while in subpopulation SAS AF= 0.0232 (112/4830). AF 95% confidence interval is 0.0197. There are 5 homozygotes in gnomad4. There are 302 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.1244A>G	p.Lys415Arg	missense_variant	8/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.1244A>G	p.Lys415Arg	missense_variant	9/80
DNAH1	XM_017006130.2	c.1244A>G	p.Lys415Arg	missense_variant	9/79
DNAH1	XM_017006131.2	c.1244A>G	p.Lys415Arg	missense_variant	9/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.1244A>G	p.Lys415Arg	missense_variant	8/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.1505A>G		non_coding_transcript_exon_variant	8/77	2
DNAH1	ENST00000497875.1	n.1409A>G		non_coding_transcript_exon_variant	9/21	2

Frequencies

GnomAD3 genomes AF: 0.00391 AC: 595 AN: 152244 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00904

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00473

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00586 AC: 1456 AN: 248352 Hom.: 10 AF XY: 0.00687 AC XY: 926 AN XY: 134820

Gnomad AFR exome AF: 0.000842

Gnomad AMR exome AF: 0.00241

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.00673

Gnomad SAS exome AF: 0.0231

Gnomad FIN exome AF: 0.00158

Gnomad NFE exome AF: 0.00414

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00586 AC: 8570 AN: 1461620 Hom.: 66 Cov.: 32 AF XY: 0.00639 AC XY: 4647 AN XY: 727086

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.00161

Gnomad4 EAS exome AF: 0.00695

Gnomad4 SAS exome AF: 0.0233

Gnomad4 FIN exome AF: 0.00150

Gnomad4 NFE exome AF: 0.00510

Gnomad4 OTH exome AF: 0.00568

GnomAD4 genome AF: 0.00390 AC: 594 AN: 152362 Hom.: 5 Cov.: 32 AF XY: 0.00405 AC XY: 302 AN XY: 74506

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00906

Gnomad4 SAS AF: 0.0232

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00472

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00401 Hom.: 7

Bravo AF: 0.00311

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000703 AC: 3

ESP6500EA AF: 0.00367 AC: 31

ExAC AF: 0.00628 AC: 760

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.00403

EpiControl AF: 0.00492

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 25, 2023	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Uncertain	0.98
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.079
Sift	Benign	0.54	T
Sift4G	Benign	0.61	T
Vest4		0.18
MVP		0.25
MPC		0.10
ClinPred		0.015	T
GERP RS		4.4
gMVP		0.34

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: rs61729402; hg19: chr3-52366368;