rs760063063

Variant names:

• chr3-52392692-C-A
• rs760063063
• NM_015512.5:c.10278+3C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-52392692-C-A
• chr3-52392692-C-G
• chr3-52392692-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015512.5(DNAH1):​c.10278+3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,441,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DNAH1 NM_015512.5 splice_region, intron
• Scores: Splicing: ADA: 0.0001990
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.92
• 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: Labcorp Genetics (formerly Invitae), ClinGen
• ciliary dyskinesia, primary, 37

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH1	NM_015512.5	MANE Select	c.10278+3C>A		splice_region intron	N/A	NP_056327.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH1	ENST00000420323.7	TSL:1 MANE Select	c.10278+3C>A		splice_region intron	N/A	ENSP00000401514.2	Q9P2D7-4
	DNAH1	ENST00000486752.5	TSL:2	n.10735+3C>A		splice_region intron	N/A
	DNAH1	ENST00000488988.5	TSL:2	n.2064+3C>A		splice_region intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1441840 Hom.: 0 Cov.: 33 AF XY: 0.00000140 AC XY: 1 AN XY: 715272

⚠️ 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: 33088

American (AMR) AF: 0.00 AC: 0 AN: 41270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25716

East Asian (EAS) AF: 0.00 AC: 0 AN: 38602

South Asian (SAS) AF: 0.0000357 AC: 3 AN: 84144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102208

Other (OTH) AF: 0.00 AC: 0 AN: 59748

⚠️ 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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.76
DANN	Benign	0.60
PhyloP100		-1.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.20
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: rs760063063; hg19: chr3-52426708;