3-52350578-A-G

Variant names:

• chr3-52350578-A-G
• rs61734644
• NM_015512.5:c.2717A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000420323.7(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 ENST00000420323.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:4
• Conservation: PhyloP100: 7.67
• Publications: 14 publications found

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]

DNAH1 Gene-Disease associations (from GenCC):

• spermatogenic failure 18

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• ciliary dyskinesia, primary, 37

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic male infertility due to sperm motility disorder

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000420323.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH1	NM_015512.5	MANE Select	c.2717A>G	p.Asp906Gly	missense	Exon 16 of 78	NP_056327.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH1	ENST00000420323.7	TSL:1 MANE Select	c.2717A>G	p.Asp906Gly	missense	Exon 16 of 78	ENSP00000401514.2
	DNAH1	ENST00000486752.5	TSL:2	n.2978A>G		non_coding_transcript_exon	Exon 16 of 77
	DNAH1	ENST00000497875.1	TSL:2	n.2882A>G		non_coding_transcript_exon	Exon 17 of 21

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

GnomAD2 exomes AF: 0.00445 AC: 1106 AN: 248652 AF XY: 0.00423

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 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

African (AFR) AF: 0.00108 AC: 36 AN: 33480

American (AMR) AF: 0.00190 AC: 85 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00528 AC: 138 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86190

European-Finnish (FIN) AF: 0.00436 AC: 233 AN: 53388

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00864 AC: 9601 AN: 1111714

Other (OTH) AF: 0.00704 AC: 425 AN: 60360

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

African (AFR) AF: 0.000890 AC: 37 AN: 41550

American (AMR) AF: 0.00150 AC: 23 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00635 AC: 22 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00264 AC: 28 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00753 AC: 512 AN: 68016

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00642 Hom.: 10

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

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	-	Premature ovarian insufficiency (1)
-	-	1	Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		7.7
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
Mutation Taster		=63/37	polymorphism

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

Other links and lift over

dbSNP: rs61734644; hg19: chr3-52384594;