rs201752275

Variant names:

• chr3-52392627-G-A
• rs201752275
• NM_015512.5:c.10216G>A

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.10216G>A​(p.Val3406Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00271 in 1,613,144 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V3406L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (14 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.49
• Publications: 9 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=0.011325091).
• BP6: Variant 3-52392627-G-A is Benign according to our data. Variant chr3-52392627-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 478381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00187 (285/152262) while in subpopulation AMR AF = 0.00458 (70/15298). AF 95% confidence interval is 0.00371. There are 0 homozygotes in GnomAd4. There are 157 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 14 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.10216G>A	p.Val3406Ile	missense	Exon 64 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.10216G>A	p.Val3406Ile	missense	Exon 64 of 78	ENSP00000401514.2	Q9P2D7-4
	DNAH1	ENST00000486752.5	TSL:2	n.10673G>A		non_coding_transcript_exon	Exon 63 of 77
	DNAH1	ENST00000488988.5	TSL:2	n.2002G>A		non_coding_transcript_exon	Exon 11 of 25

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 285 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00384

GnomAD2 exomes AF: 0.00266 AC: 656 AN: 246858 AF XY: 0.00295

Gnomad AFR exome AF: 0.000394

Gnomad AMR exome AF: 0.00307

Gnomad ASJ exome AF: 0.00250

Gnomad EAS exome AF: 0.0000560

Gnomad FIN exome AF: 0.000326

Gnomad NFE exome AF: 0.00294

Gnomad OTH exome AF: 0.00367

GnomAD4 exome AF: 0.00280 AC: 4090 AN: 1460882 Hom.: 14 Cov.: 33 AF XY: 0.00291 AC XY: 2111 AN XY: 726658

African (AFR) AF: 0.000627 AC: 21 AN: 33472

American (AMR) AF: 0.00298 AC: 133 AN: 44570

Ashkenazi Jewish (ASJ) AF: 0.00237 AC: 62 AN: 26108

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39680

South Asian (SAS) AF: 0.00553 AC: 476 AN: 86076

European-Finnish (FIN) AF: 0.000319 AC: 17 AN: 53316

Middle Eastern (MID) AF: 0.00815 AC: 47 AN: 5766

European-Non Finnish (NFE) AF: 0.00280 AC: 3107 AN: 1111548

Other (OTH) AF: 0.00373 AC: 225 AN: 60346

GnomAD4 genome AF: 0.00187 AC: 285 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.00211 AC XY: 157 AN XY: 74444

African (AFR) AF: 0.000313 AC: 13 AN: 41544

American (AMR) AF: 0.00458 AC: 70 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00231 AC: 157 AN: 68010

Other (OTH) AF: 0.00380 AC: 8 AN: 2104

Alfa AF: 0.00266 Hom.: 3

Bravo AF: 0.00212

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000244 AC: 1

ESP6500EA AF: 0.00310 AC: 26

ExAC AF: 0.00264 AC: 319

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely 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
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.39	T
PhyloP100		3.5
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.19
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.051	T
Vest4		0.46
MVP		0.62
MPC		0.44
ClinPred		0.017	T
GERP RS		4.5
gMVP		0.58
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: rs201752275; hg19: chr3-52426643;