chr3-52396682-G-A

Variant names:

• chr3-52396682-G-A
• rs365048
• NM_015512.5:c.11495G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_015512.5(DNAH1):​c.11495G>A​(p.Arg3832His) variant causes a missense change. The variant allele was found at a frequency of 0.00121 in 1,613,718 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3832C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0046 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (6 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.65
• Publications: 26 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16767171).
• BP6: Variant 3-52396682-G-A is Benign according to our data. Variant chr3-52396682-G-A is described in ClinVar as Benign. ClinVar VariationId is 478401.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00463 (704/152214) while in subpopulation AFR AF = 0.0157 (653/41502). AF 95% confidence interval is 0.0147. There are 7 homozygotes in GnomAd4. There are 330 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD gene

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.11495G>A	p.Arg3832His	missense	Exon 72 of 78	NP_056327.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH1	ENST00000420323.7	TSL:1 MANE Select	c.11495G>A	p.Arg3832His	missense	Exon 72 of 78	ENSP00000401514.2	Q9P2D7-4
	DNAH1	ENST00000486752.5	TSL:2	n.11952G>A		non_coding_transcript_exon	Exon 71 of 77
	DNAH1	ENST00000488988.5	TSL:2	n.3281G>A		non_coding_transcript_exon	Exon 19 of 25

Frequencies

GnomAD3 genomes AF: 0.00462 AC: 703 AN: 152096 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00480

GnomAD4 exome AF: 0.000854 AC: 1248 AN: 1461504 Hom.: 6 Cov.: 34 AF XY: 0.000816 AC XY: 593 AN XY: 727018

African (AFR) AF: 0.0187 AC: 625 AN: 33480

American (AMR) AF: 0.000559 AC: 25 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53224

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000480 AC: 534 AN: 1111856

Other (OTH) AF: 0.000928 AC: 56 AN: 60370

GnomAD4 genome AF: 0.00463 AC: 704 AN: 152214 Hom.: 7 Cov.: 32 AF XY: 0.00443 AC XY: 330 AN XY: 74430

African (AFR) AF: 0.0157 AC: 653 AN: 41502

American (AMR) AF: 0.00144 AC: 22 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68020

Other (OTH) AF: 0.00475 AC: 10 AN: 2106

Alfa AF: 0.00179 Hom.: 10

Bravo AF: 0.00538

ClinVar

ClinVar submissions

Significance: Benign

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
AlphaMissense	Uncertain	0.51
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	30
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.17	T
PhyloP100		3.6
Sift4G	Uncertain	0.0020	D
Vest4		0.63
gMVP		0.80

Splicing

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

Other links and lift over

dbSNP: rs365048; hg19: chr3-52430698;