rs61734644

Positions:

• chr3-52350578-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.2717A>G​(p.Asp906Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00691 in 1,613,708 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0072 (47 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: 7.67

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=0.008781254).
• BP6: Variant 3-52350578-A-G is Benign according to our data. Variant chr3-52350578-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 478433.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 = 0.00412 (627/152284) while in subpopulation NFE AF= 0.00753 (512/68016). AF 95% confidence interval is 0.00699. There are 4 homozygotes in gnomad4. There are 287 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.2717A>G	p.Asp906Gly	missense_variant	16/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.2717A>G	p.Asp906Gly	missense_variant	17/80
DNAH1	XM_017006130.2	c.2717A>G	p.Asp906Gly	missense_variant	17/79
DNAH1	XM_017006131.2	c.2717A>G	p.Asp906Gly	missense_variant	17/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.2717A>G	p.Asp906Gly	missense_variant	16/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.2978A>G		non_coding_transcript_exon_variant	16/77	2
DNAH1	ENST00000497875.1	n.2882A>G		non_coding_transcript_exon_variant	17/21	2

Frequencies

GnomAD3 genomes AF: 0.00412 AC: 627 AN: 152166 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00635

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00753

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00445 AC: 1106 AN: 248652 Hom.: 5 AF XY: 0.00423 AC XY: 571 AN XY: 134896

Gnomad AFR exome AF: 0.000844

Gnomad AMR exome AF: 0.00209

Gnomad ASJ exome AF: 0.00458

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00451

Gnomad NFE exome AF: 0.00755

Gnomad OTH exome AF: 0.00430

GnomAD4 exome AF: 0.00720 AC: 10527 AN: 1461424 Hom.: 47 Cov.: 31 AF XY: 0.00691 AC XY: 5022 AN XY: 726972

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.00528

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00436

Gnomad4 NFE exome AF: 0.00864

Gnomad4 OTH exome AF: 0.00704

GnomAD4 genome AF: 0.00412 AC: 627 AN: 152284 Hom.: 4 Cov.: 33 AF XY: 0.00385 AC XY: 287 AN XY: 74460

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00635

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.00753

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00679 Hom.: 4

Bravo AF: 0.00397

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.000738 AC: 3

ESP6500EA AF: 0.00690 AC: 58

ExAC AF: 0.00438 AC: 530

EpiCase AF: 0.00883

EpiControl AF: 0.00730

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	DNAH1: BS2 -

Premature ovarian insufficiency Uncertain:1

Uncertain significance, no assertion criteria provided

research

Reproductive Development, Murdoch Childrens Research Institute

Jan 10, 2018

- -

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	Pathogenic	0.82
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0070	D
Vest4		0.75
MVP		0.45
MPC		0.28
ClinPred		0.026	T
GERP RS		4.7
gMVP		0.87

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: rs61734644; hg19: chr3-52384594;