chr3-52386299-C-T

Variant names:

• chr3-52386299-C-T
• rs182141515
• NM_015512.5:c.8765C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015512.5(DNAH1):​c.8765C>T​(p.Ala2922Val) variant causes a missense change. The variant allele was found at a frequency of 0.00323 in 1,601,892 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A2922A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (10 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.97
• Publications: 7 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 (MetaRNN=0.014848143).
• BP6: Variant 3-52386299-C-T is Benign according to our data. Variant chr3-52386299-C-T is described in ClinVar as Benign. ClinVar VariationId is 478504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00214 (326/152364) while in subpopulation NFE AF = 0.00401 (273/68030). AF 95% confidence interval is 0.00362. There are 0 homozygotes in GnomAd4. There are 136 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 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.8765C>T	p.Ala2922Val	missense	Exon 55 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.8765C>T	p.Ala2922Val	missense	Exon 55 of 78	ENSP00000401514.2	Q9P2D7-4
	DNAH1	ENST00000486752.5	TSL:2	n.9026C>T		non_coding_transcript_exon	Exon 55 of 77
	DNAH1	ENST00000488988.5	TSL:2	n.355C>T		non_coding_transcript_exon	Exon 3 of 25

Frequencies

GnomAD3 genomes AF: 0.00215 AC: 327 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00403

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00227 AC: 507 AN: 223620 AF XY: 0.00218

Gnomad AFR exome AF: 0.000463

Gnomad AMR exome AF: 0.00141

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000796

Gnomad NFE exome AF: 0.00367

Gnomad OTH exome AF: 0.00161

GnomAD4 exome AF: 0.00334 AC: 4846 AN: 1449528 Hom.: 10 Cov.: 31 AF XY: 0.00324 AC XY: 2330 AN XY: 720064

African (AFR) AF: 0.000602 AC: 20 AN: 33208

American (AMR) AF: 0.00121 AC: 52 AN: 42804

Ashkenazi Jewish (ASJ) AF: 0.0000387 AC: 1 AN: 25862

East Asian (EAS) AF: 0.00 AC: 0 AN: 38934

South Asian (SAS) AF: 0.00208 AC: 175 AN: 84332

European-Finnish (FIN) AF: 0.00109 AC: 57 AN: 52132

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5746

European-Non Finnish (NFE) AF: 0.00397 AC: 4395 AN: 1106584

Other (OTH) AF: 0.00240 AC: 144 AN: 59926

GnomAD4 genome AF: 0.00214 AC: 326 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.00183 AC XY: 136 AN XY: 74498

African (AFR) AF: 0.000409 AC: 17 AN: 41582

American (AMR) AF: 0.000784 AC: 12 AN: 15312

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4832

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00401 AC: 273 AN: 68030

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00302 Hom.: 1

Bravo AF: 0.00190

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000233 AC: 1

ESP6500EA AF: 0.00402 AC: 34

ExAC AF: 0.00215 AC: 260

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	DNAH1-related disorder (1)
-	-	1	not provided (1)
-	-	1	Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Uncertain	1.0
Eigen	Benign	0.086
Eigen_PC	Benign	0.0056
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	-0.13	T
PhyloP100		4.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.38
Sift	Benign	0.049	D
Sift4G	Benign	0.090	T
Vest4		0.63
MVP		0.61
MPC		0.16
ClinPred		0.051	T
GERP RS		3.6
gMVP		0.55
Mutation Taster		=94/6	polymorphism

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: rs182141515; hg19: chr3-52420315; COSMIC: COSV70234377; COSMIC: COSV70234377;