chr3-52346479-T-C

Variant names:

• chr3-52346479-T-C
• rs1553631684
• NM_015512.5:c.1664T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015512.5(DNAH1):​c.1664T>C​(p.Met555Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.52
• Publications: 0 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: ClinGen, Labcorp Genetics (formerly Invitae)
• ciliary dyskinesia, primary, 37

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4112834).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.1664T>C	p.Met555Thr	missense_variant	Exon 11 of 78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.1664T>C	p.Met555Thr	missense_variant	Exon 12 of 80		XP_016861618.1
DNAH1	XM_017006130.2	c.1664T>C	p.Met555Thr	missense_variant	Exon 12 of 79		XP_016861619.1
DNAH1	XM_017006131.2	c.1664T>C	p.Met555Thr	missense_variant	Exon 12 of 79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.1664T>C	p.Met555Thr	missense_variant	Exon 11 of 78	1	NM_015512.5	ENSP00000401514.2
DNAH1	ENST00000486752.5	n.1925T>C		non_coding_transcript_exon_variant	Exon 11 of 77	2
DNAH1	ENST00000497875.1	n.1829T>C		non_coding_transcript_exon_variant	Exon 12 of 21	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Sep 10, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with DNAH1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with threonine at codon 555 of the DNAH1 protein (p.Met555Thr). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Benign	0.89
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.092
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-1.0	T
PhyloP100		3.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.062
Sift	Benign	0.72	T
Sift4G	Benign	0.70	T
Vest4		0.64
MutPred		0.63		Loss of stability (P = 0.0469);
MVP		0.21
MPC		0.14
ClinPred		0.36	T
GERP RS		4.6
gMVP		0.41
Mutation Taster		=81/19	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: rs1553631684; hg19: chr3-52380495;