chr3-52322612-C-T

Position:

• chr3-52322612-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015512.5(DNAH1):​c.170C>T​(p.Pro57Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.141

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.070070356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.170C>T	p.Pro57Leu	missense_variant	2/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.170C>T	p.Pro57Leu	missense_variant	3/80
DNAH1	XM_017006130.2	c.170C>T	p.Pro57Leu	missense_variant	3/79
DNAH1	XM_017006131.2	c.170C>T	p.Pro57Leu	missense_variant	3/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.170C>T	p.Pro57Leu	missense_variant	2/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.431C>T		non_coding_transcript_exon_variant	2/77	2
DNAH1	ENST00000497875.1	n.335C>T		non_coding_transcript_exon_variant	3/21	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461676 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2018

This sequence change replaces proline with leucine at codon 57 of the DNAH1 protein (p.Pro57Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DNAH1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Benign	0.95
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.047
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.054	T
Vest4		0.22
MutPred		0.17		Loss of relative solvent accessibility (P = 0.0414);
MVP		0.12
MPC		0.13
ClinPred		0.15	T
GERP RS		1.4
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1559485379; hg19: chr3-52356628;