rs1131692234

Variant names:

• chr3-52397706-G-A
• rs1131692234
• NM_015512.5:c.11788-1G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_015512.5(DNAH1):​c.11788-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,450,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DNAH1 NM_015512.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.73
• Publications: 1 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 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.013361462 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.3, offset of 1, new splice context is: ttggcctcctctctcctaAGgct. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-52397706-G-A is Pathogenic according to our data. Variant chr3-52397706-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 430855.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.11788-1G>A		splice_acceptor_variant, intron_variant	Intron 73 of 77	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.11857-1G>A		splice_acceptor_variant, intron_variant	Intron 75 of 79		XP_016861618.1
DNAH1	XM_017006130.2	c.11788-1G>A		splice_acceptor_variant, intron_variant	Intron 74 of 78		XP_016861619.1
DNAH1	XM_017006131.2	c.11731-1G>A		splice_acceptor_variant, intron_variant	Intron 74 of 78		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.11788-1G>A		splice_acceptor_variant, intron_variant	Intron 73 of 77	1	NM_015512.5	ENSP00000401514.2
DNAH1	ENST00000486752.5	n.12245-1G>A		splice_acceptor_variant, intron_variant	Intron 72 of 76	2
DNAH1	ENST00000488988.5	n.3574-1G>A		splice_acceptor_variant, intron_variant	Intron 20 of 24	2
DNAH1	ENST00000490713.5	n.2488-1G>A		splice_acceptor_variant, intron_variant	Intron 16 of 19	5		ENSP00000419071.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1450002 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 720566

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33256

American (AMR) AF: 0.00 AC: 0 AN: 43342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25142

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 84114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52826

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106040

Other (OTH) AF: 0.00 AC: 0 AN: 59900

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Spermatogenic failure 18 Pathogenic:1

Jul 20, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.7
GERP RS		5.3
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: 2
DS_AL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1131692234; hg19: chr3-52431722; COSMIC: COSV56231587; COSMIC: COSV56231587;