3-52372236-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.6676A>G(p.Ile2226Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00696 in 1,613,864 control chromosomes in the GnomAD database, including 55 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0071 (48 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.910

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=0.011133552).
• BP6: Variant 3-52372236-A-G is Benign according to our data. Variant chr3-52372236-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 478481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00528 (804/152294) while in subpopulation NFE AF= 0.00831 (565/68016). AF 95% confidence interval is 0.00774. There are 7 homozygotes in gnomad4. There are 393 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.6676A>G	p.Ile2226Val	missense_variant	43/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.6745A>G	p.Ile2249Val	missense_variant	45/80
DNAH1	XM_017006130.2	c.6676A>G	p.Ile2226Val	missense_variant	44/79
DNAH1	XM_017006131.2	c.6745A>G	p.Ile2249Val	missense_variant	45/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.6676A>G	p.Ile2226Val	missense_variant	43/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.6937A>G		non_coding_transcript_exon_variant	43/77	2

Frequencies

GnomAD3 genomes AF: 0.00528 AC: 803 AN: 152176 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.0429

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.00574

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00831

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00557 AC: 1385 AN: 248732 Hom.: 3 AF XY: 0.00592 AC XY: 799 AN XY: 134994

Gnomad AFR exome AF: 0.00104

Gnomad AMR exome AF: 0.00215

Gnomad ASJ exome AF: 0.00578

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00549

Gnomad FIN exome AF: 0.00684

Gnomad NFE exome AF: 0.00792

Gnomad OTH exome AF: 0.00464

GnomAD4 exome AF: 0.00714 AC: 10433 AN: 1461570 Hom.: 48 Cov.: 32 AF XY: 0.00718 AC XY: 5223 AN XY: 727074

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.00624

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00580

Gnomad4 FIN exome AF: 0.00633

Gnomad4 NFE exome AF: 0.00794

Gnomad4 OTH exome AF: 0.00726

GnomAD4 genome AF: 0.00528 AC: 804 AN: 152294 Hom.: 7 Cov.: 33 AF XY: 0.00528 AC XY: 393 AN XY: 74488

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00606

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00455

Gnomad4 FIN AF: 0.00574

Gnomad4 NFE AF: 0.00831

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00731 Hom.: 4

Bravo AF: 0.00484

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00117 AC: 5

ESP6500EA AF: 0.00868 AC: 74

ExAC AF: 0.00580 AC: 703

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00714

EpiControl AF: 0.00871

ClinVar

Significance: 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	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	DNAH1: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	8.6
Dann	Benign	0.68
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.98	D
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.017
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.27
MVP		0.13
MPC		0.10
ClinPred		0.000035	T
GERP RS		1.9
gMVP		0.29

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: rs112505934; hg19: chr3-52406252; COSMIC: COSV99066692; COSMIC: COSV99066692;