rs201455697

Positions:

• chr3-52353277-G-A
• chr3-52353277-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_015512.5(DNAH1):​c.3202G>A​(p.Val1068Met) variant causes a missense change. The variant allele was found at a frequency of 0.000737 in 1,613,818 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (2 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 4.70

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03922695).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.3202G>A	p.Val1068Met	missense_variant	19/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.3202G>A	p.Val1068Met	missense_variant	20/80
DNAH1	XM_017006130.2	c.3202G>A	p.Val1068Met	missense_variant	20/79
DNAH1	XM_017006131.2	c.3202G>A	p.Val1068Met	missense_variant	20/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.3202G>A	p.Val1068Met	missense_variant	19/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.3463G>A		non_coding_transcript_exon_variant	19/77	2
DNAH1	ENST00000497875.1	n.3367G>A		non_coding_transcript_exon_variant	20/21	2

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000627 AC: 156 AN: 248738 Hom.: 0 AF XY: 0.000593 AC XY: 80 AN XY: 134922

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000648

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000775 AC: 1133 AN: 1461594 Hom.: 2 Cov.: 31 AF XY: 0.000740 AC XY: 538 AN XY: 727082

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000545

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000870

Gnomad4 OTH exome AF: 0.000828

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.000323 AC XY: 24 AN XY: 74360

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000515 Hom.: 0

Bravo AF: 0.000412

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000235 AC: 1

ESP6500EA AF: 0.000706 AC: 6

ExAC AF: 0.000635 AC: 77

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 09, 2023	BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 10, 2021	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 24, 2023

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1068 of the DNAH1 protein (p.Val1068Met). This variant is present in population databases (rs201455697, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with DNAH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 577602). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DNAH1 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

DNAH1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 08, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.070
Sift	Benign	0.17	T
Sift4G	Benign	0.23	T
Vest4		0.57
MVP		0.51
MPC		0.15
ClinPred		0.011	T
GERP RS		5.5
gMVP		0.39

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: rs201455697; hg19: chr3-52387293;