rs1268954616

Variant names:

• chr3-52361161-C-A
• rs1268954616
• NM_015512.5:c.4686-3C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-52361161-C-A
• chr3-52361161-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.4686-3C>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 0.000000695 in 1,437,820 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: DNAH1 NM_015512.5 splice_region, intron
• Scores: Splicing: ADA: 0.3303
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.306
• 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=-0.66).

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.4686-3C>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.4686-3C>A		splice_region intron	N/A	ENSP00000401514.2	Q9P2D7-4
	DNAH1	ENST00000486752.5	TSL:2	n.4947-3C>A		splice_region intron	N/A
	DNAH1	ENST00000466628.1	TSL:5	n.-58C>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1437820 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 714038

⚠️ 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: 32590

American (AMR) AF: 0.00 AC: 0 AN: 40874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24972

East Asian (EAS) AF: 0.00 AC: 0 AN: 38996

South Asian (SAS) AF: 0.00 AC: 0 AN: 82156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1101192

Other (OTH) AF: 0.00 AC: 0 AN: 59330

⚠️ 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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Benign	0.77
PhyloP100		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.33
dbscSNV1_RF	Benign	0.41
SpliceAI score (max)		0.090		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: rs1268954616; hg19: chr3-52395177;