NM_015512.5:c.6139-15G>A

Variant names:

• chr3-52370095-G-A
• rs746239
• NM_015512.5:c.6139-15G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015512.5(DNAH1):​c.6139-15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,613,830 control chromosomes in the GnomAD database, including 10,867 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (631 hom., cov: 33)
  • Exomes 𝑓: 0.11 (10236 hom.)
• Consequence: DNAH1 NM_015512.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.325
• Publications: 11 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-52370095-G-A is Benign according to our data. Variant chr3-52370095-G-A is described in ClinVar as Benign. ClinVar VariationId is 402600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

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.6139-15G>A		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.6139-15G>A		intron	N/A	ENSP00000401514.2	Q9P2D7-4
	DNAH1	ENST00000486752.5	TSL:2	n.6400-15G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0822 AC: 12504 AN: 152170 Hom.: 632 Cov.: 33

Gnomad AFR AF: 0.0354

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0753

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0658

Gnomad FIN AF: 0.0527

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.104

GnomAD2 exomes AF: 0.0851 AC: 21189 AN: 248960 AF XY: 0.0861

Gnomad AFR exome AF: 0.0350

Gnomad AMR exome AF: 0.0642

Gnomad ASJ exome AF: 0.120

Gnomad EAS exome AF: 0.000223

Gnomad FIN exome AF: 0.0564

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.0933

GnomAD4 exome AF: 0.113 AC: 164725 AN: 1461542 Hom.: 10236 Cov.: 33 AF XY: 0.111 AC XY: 81007 AN XY: 727068

African (AFR) AF: 0.0371 AC: 1242 AN: 33478

American (AMR) AF: 0.0672 AC: 3005 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 3162 AN: 26130

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39698

South Asian (SAS) AF: 0.0751 AC: 6479 AN: 86254

European-Finnish (FIN) AF: 0.0593 AC: 3163 AN: 53356

Middle Eastern (MID) AF: 0.100 AC: 579 AN: 5768

European-Non Finnish (NFE) AF: 0.126 AC: 140638 AN: 1111778

Other (OTH) AF: 0.107 AC: 6445 AN: 60372

GnomAD4 genome AF: 0.0821 AC: 12505 AN: 152288 Hom.: 631 Cov.: 33 AF XY: 0.0791 AC XY: 5888 AN XY: 74446

African (AFR) AF: 0.0354 AC: 1471 AN: 41566

American (AMR) AF: 0.0752 AC: 1150 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 440 AN: 3470

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5190

South Asian (SAS) AF: 0.0665 AC: 321 AN: 4828

European-Finnish (FIN) AF: 0.0527 AC: 560 AN: 10624

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8245 AN: 67992

Other (OTH) AF: 0.103 AC: 217 AN: 2110

Alfa AF: 0.0991 Hom.: 162

Bravo AF: 0.0812

Asia WGS AF: 0.0280 AC: 99 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.64
DANN	Benign	0.75
PhyloP100		0.33
Mutation Taster		=100/0	polymorphism (auto)

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: rs746239; hg19: chr3-52404111;