rs28434358

chr3-52383578-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.8134A>G(p.Met2712Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,594,326 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (33 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (32 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.421

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=0.0033148527).
• BP6: Variant 3-52383578-A-G is Benign according to our data. Variant chr3-52383578-A-G is described in ClinVar as [Benign]. Clinvar id is 478497.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0113 (1725/152368) while in subpopulation AFR AF= 0.0388 (1614/41590). AF 95% confidence interval is 0.0372. There are 33 homozygotes in gnomad4. There are 839 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.8134A>G	p.Met2712Val	missense_variant	51/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.8203A>G	p.Met2735Val	missense_variant	53/80
DNAH1	XM_017006130.2	c.8134A>G	p.Met2712Val	missense_variant	52/79
DNAH1	XM_017006131.2	c.8203A>G	p.Met2735Val	missense_variant	53/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.8134A>G	p.Met2712Val	missense_variant	51/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.8395A>G		non_coding_transcript_exon_variant	51/77	2

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1715 AN: 152250 Hom.: 33 Cov.: 33

Gnomad AFR AF: 0.0387

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00333 AC: 722 AN: 216568 Hom.: 9 AF XY: 0.00270 AC XY: 317 AN XY: 117268

Gnomad AFR exome AF: 0.0440

Gnomad AMR exome AF: 0.00169

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00238

Gnomad FIN exome AF: 0.0000518

Gnomad NFE exome AF: 0.000436

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00154 AC: 2221 AN: 1441958 Hom.: 32 Cov.: 31 AF XY: 0.00143 AC XY: 1020 AN XY: 715390

Gnomad4 AFR exome AF: 0.0389

Gnomad4 AMR exome AF: 0.00184

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00247

Gnomad4 FIN exome AF: 0.0000773

Gnomad4 NFE exome AF: 0.000419

Gnomad4 OTH exome AF: 0.00282

GnomAD4 genome AF: 0.0113 AC: 1725 AN: 152368 Hom.: 33 Cov.: 33 AF XY: 0.0113 AC XY: 839 AN XY: 74518

Gnomad4 AFR AF: 0.0388

Gnomad4 AMR AF: 0.00300

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00233 Hom.: 6

Bravo AF: 0.0128

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0355 AC: 152

ESP6500EA AF: 0.000944 AC: 8

ExAC AF: 0.00376 AC: 454

Asia WGS AF: 0.00115 AC: 4 AN: 3478

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	Benign	0.069
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	4.7
Dann	Benign	0.62
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.85	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.065
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.33
MVP		0.13
MPC		0.13
ClinPred		0.0043	T
GERP RS		-0.99
gMVP		0.32

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: rs28434358; hg19: chr3-52417594;