rs13060192

Positions:

• chr3-52344524-G-C

Variant summary

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

The NM_015512.5(DNAH1):​c.1321G>C​(p.Val441Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0439 in 1,613,970 control chromosomes in the GnomAD database, including 1,787 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (145 hom., cov: 33)
  • Exomes 𝑓: 0.045 (1642 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.45

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=0.0024633408).
• BP6: Variant 3-52344524-G-C is Benign according to our data. Variant chr3-52344524-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 478413.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 = 0.0364 (5544/152334) while in subpopulation AMR AF= 0.0485 (743/15306). AF 95% confidence interval is 0.0468. There are 145 homozygotes in gnomad4. There are 2551 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 145 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.1321G>C	p.Val441Leu	missense_variant	9/78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.1321G>C	p.Val441Leu	missense_variant	10/80		XP_016861618.1
DNAH1	XM_017006130.2	c.1321G>C	p.Val441Leu	missense_variant	10/79		XP_016861619.1
DNAH1	XM_017006131.2	c.1321G>C	p.Val441Leu	missense_variant	10/79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.1321G>C	p.Val441Leu	missense_variant	9/78	1	NM_015512.5	ENSP00000401514.2
DNAH1	ENST00000486752.5	n.1582G>C		non_coding_transcript_exon_variant	9/77	2
DNAH1	ENST00000497875.1	n.1486G>C		non_coding_transcript_exon_variant	10/21	2

Frequencies

GnomAD3 genomes AF: 0.0364 AC: 5544 AN: 152216 Hom.: 144 Cov.: 33

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.0486

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.0227

Gnomad SAS AF: 0.0221

Gnomad FIN AF: 0.0342

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0481

Gnomad OTH AF: 0.0436

GnomAD3 exomes AF: 0.0367 AC: 9158 AN: 249218 Hom.: 206 AF XY: 0.0371 AC XY: 5017 AN XY: 135196

Gnomad AFR exome AF: 0.0157

Gnomad AMR exome AF: 0.0346

Gnomad ASJ exome AF: 0.0276

Gnomad EAS exome AF: 0.0179

Gnomad SAS exome AF: 0.0203

Gnomad FIN exome AF: 0.0365

Gnomad NFE exome AF: 0.0480

Gnomad OTH exome AF: 0.0474

GnomAD4 exome AF: 0.0447 AC: 65313 AN: 1461636 Hom.: 1642 Cov.: 31 AF XY: 0.0443 AC XY: 32222 AN XY: 727114

Gnomad4 AFR exome AF: 0.0160

Gnomad4 AMR exome AF: 0.0376

Gnomad4 ASJ exome AF: 0.0283

Gnomad4 EAS exome AF: 0.0164

Gnomad4 SAS exome AF: 0.0206

Gnomad4 FIN exome AF: 0.0375

Gnomad4 NFE exome AF: 0.0494

Gnomad4 OTH exome AF: 0.0465

GnomAD4 genome AF: 0.0364 AC: 5544 AN: 152334 Hom.: 145 Cov.: 33 AF XY: 0.0342 AC XY: 2551 AN XY: 74496

Gnomad4 AFR AF: 0.0158

Gnomad4 AMR AF: 0.0485

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.0223

Gnomad4 SAS AF: 0.0219

Gnomad4 FIN AF: 0.0342

Gnomad4 NFE AF: 0.0481

Gnomad4 OTH AF: 0.0431

Alfa AF: 0.0463 Hom.: 141

Bravo AF: 0.0374

TwinsUK AF: 0.0496 AC: 184

ALSPAC AF: 0.0472 AC: 182

ESP6500AA AF: 0.0132 AC: 55

ESP6500EA AF: 0.0467 AC: 393

ExAC AF: 0.0358 AC: 4338

Asia WGS AF: 0.0370 AC: 127 AN: 3478

EpiCase AF: 0.0491

EpiControl AF: 0.0534

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 31213628) -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.040
Sift	Benign	0.079	T
Sift4G	Benign	0.086	T
Vest4		0.15
MutPred		0.64		Gain of sheet (P = 0.0016);
MPC		0.13
ClinPred		0.016	T
GERP RS		5.0
gMVP		0.46

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: rs13060192; hg19: chr3-52378540;