rs201752275

Positions:

• chr3-52392627-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000420323.7(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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (14 hom.)
• Consequence: DNAH1 ENST00000420323.7 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.49

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.10216G>A	p.Val3406Ile	missense_variant	64/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.10285G>A	p.Val3429Ile	missense_variant	66/80		XP_016861618.1
DNAH1	XM_017006130.2	c.10216G>A	p.Val3406Ile	missense_variant	65/79		XP_016861619.1
DNAH1	XM_017006131.2	c.10159G>A	p.Val3387Ile	missense_variant	65/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.10216G>A	p.Val3406Ile	missense_variant	64/78	1	NM_015512.5	ENSP00000401514	P1
DNAH1	ENST00000486752.5	n.10673G>A		non_coding_transcript_exon_variant	63/77	2
DNAH1	ENST00000488988.5	n.2002G>A		non_coding_transcript_exon_variant	11/25	2
DNAH1	ENST00000490713.5	c.916G>A	p.Val306Ile	missense_variant, NMD_transcript_variant	7/20	5		ENSP00000419071

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

GnomAD3 exomes AF: 0.00266 AC: 656 AN: 246858 Hom.: 2 AF XY: 0.00295 AC XY: 396 AN XY: 134018

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 SAS exome AF: 0.00531

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

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00298

Gnomad4 ASJ exome AF: 0.00237

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00553

Gnomad4 FIN exome AF: 0.000319

Gnomad4 NFE exome AF: 0.00280

Gnomad4 OTH exome AF: 0.00373

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

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00458

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00231

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00283 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

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	DNAH1: BP4 -

Spermatogenic failure 18;C4539798:Ciliary dyskinesia, primary, 37 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 09, 2024

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs201752275; hg19: chr3-52426643;