3-52386666-G-T

Variant names:

• chr3-52386666-G-T
• rs749580264
• NM_015512.5:c.8816G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015512.5(DNAH1):​c.8816G>T​(p.Arg2939Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000702 in 1,425,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2939C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.03
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015512.5. 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.8816G>T	p.Arg2939Leu	missense	Exon 56 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.8816G>T	p.Arg2939Leu	missense	Exon 56 of 78	ENSP00000401514.2
	DNAH1	ENST00000486752.5	TSL:2	n.9077G>T		non_coding_transcript_exon	Exon 56 of 77
	DNAH1	ENST00000488988.5	TSL:2	n.406G>T		non_coding_transcript_exon	Exon 4 of 25

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1425222 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 705550

African (AFR) AF: 0.00 AC: 0 AN: 32600

American (AMR) AF: 0.00 AC: 0 AN: 39548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25188

East Asian (EAS) AF: 0.00 AC: 0 AN: 37818

South Asian (SAS) AF: 0.00 AC: 0 AN: 80760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5594

European-Non Finnish (NFE) AF: 9.14e-7 AC: 1 AN: 1094128

Other (OTH) AF: 0.00 AC: 0 AN: 58950

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.53	D
PhyloP100		7.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.017	D
Vest4		0.90
MutPred		0.48		Loss of MoRF binding (P = 0.0314)
MVP		0.66
MPC		0.43
ClinPred		0.99	D
GERP RS		4.2
gMVP		0.72
Mutation Taster		=45/55	disease causing

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: rs749580264; hg19: chr3-52420682;