chr3-52369976-C-G

Variant names:

• chr3-52369976-C-G
• rs199808005
• NM_015512.5:c.6095C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_015512.5(DNAH1):​c.6095C>G​(p.Pro2032Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign 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. P2032L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.12
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16862813).

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.6095C>G	p.Pro2032Arg	missense	Exon 38 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.6095C>G	p.Pro2032Arg	missense	Exon 38 of 78	ENSP00000401514.2
	DNAH1	ENST00000486752.5	TSL:2	n.6356C>G		non_coding_transcript_exon	Exon 38 of 77

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249190 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461576 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727064

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111822

Other (OTH) AF: 0.0000166 AC: 1 AN: 60368

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Benign	0.97
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
PhyloP100		3.1
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Benign	0.063
Sift	Benign	0.17	T
Sift4G	Benign	0.17	T
Vest4		0.32
MutPred		0.39		Loss of helix (P = 0.0138)
MVP		0.28
MPC		0.14
ClinPred		0.40	T
GERP RS		3.5
gMVP		0.55
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: rs199808005; hg19: chr3-52403992;