3-52332280-A-G

Position:

• chr3-52332280-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_015512.5(DNAH1):​c.1172A>G​(p.Tyr391Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00302 in 1,614,064 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (16 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.19

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01452148).
• BP6: Variant 3-52332280-A-G is Benign according to our data. Variant chr3-52332280-A-G is described in ClinVar as [Benign]. Clinvar id is 478403.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00259 (394/152372) while in subpopulation NFE AF= 0.00319 (217/68034). AF 95% confidence interval is 0.00284. There are 2 homozygotes in gnomad4. There are 194 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.1172A>G	p.Tyr391Cys	missense_variant	8/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.1172A>G	p.Tyr391Cys	missense_variant	9/80
DNAH1	XM_017006130.2	c.1172A>G	p.Tyr391Cys	missense_variant	9/79
DNAH1	XM_017006131.2	c.1172A>G	p.Tyr391Cys	missense_variant	9/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.1172A>G	p.Tyr391Cys	missense_variant	8/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.1433A>G		non_coding_transcript_exon_variant	8/77	2
DNAH1	ENST00000497875.1	n.1337A>G		non_coding_transcript_exon_variant	9/21	2

Frequencies

GnomAD3 genomes AF: 0.00259 AC: 394 AN: 152254 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00997

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00319

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00240 AC: 597 AN: 249136 Hom.: 3 AF XY: 0.00235 AC XY: 317 AN XY: 135154

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.00477

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000752

Gnomad FIN exome AF: 0.00724

Gnomad NFE exome AF: 0.00293

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00307 AC: 4483 AN: 1461692 Hom.: 16 Cov.: 32 AF XY: 0.00295 AC XY: 2145 AN XY: 727122

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00494

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000475

Gnomad4 FIN exome AF: 0.00811

Gnomad4 NFE exome AF: 0.00329

Gnomad4 OTH exome AF: 0.00292

GnomAD4 genome AF: 0.00259 AC: 394 AN: 152372 Hom.: 2 Cov.: 32 AF XY: 0.00260 AC XY: 194 AN XY: 74516

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00997

Gnomad4 NFE AF: 0.00319

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00274 Hom.: 4

Bravo AF: 0.00187

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00115 AC: 5

ESP6500EA AF: 0.00352 AC: 30

ExAC AF: 0.00233 AC: 282

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00213

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	Uncertain	0.51
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Benign	0.22
Sift	Benign	0.042	D
Sift4G	Uncertain	0.028	D
Vest4		0.67
MVP		0.37
MPC		0.17
ClinPred		0.051	T
GERP RS		4.7
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs181418923; hg19: chr3-52366296;