rs866647249

Positions:

• chr3-52394526-C-A
• chr3-52394526-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015512.5(DNAH1):​c.10688C>A​(p.Pro3563Gln) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P3563L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.488

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28199154).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.10688C>A	p.Pro3563Gln	missense_variant	67/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.10757C>A	p.Pro3586Gln	missense_variant	69/80
DNAH1	XM_017006130.2	c.10688C>A	p.Pro3563Gln	missense_variant	68/79
DNAH1	XM_017006131.2	c.10631C>A	p.Pro3544Gln	missense_variant	68/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.10688C>A	p.Pro3563Gln	missense_variant	67/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.11145C>A		non_coding_transcript_exon_variant	66/77	2
DNAH1	ENST00000488988.5	n.2474C>A		non_coding_transcript_exon_variant	14/25	2
DNAH1	ENST00000490713.5	c.1388C>A	p.Pro463Gln	missense_variant, NMD_transcript_variant	10/20	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	11
DANN	Uncertain	0.99
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.86	D
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	-0.21	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.029	D
Vest4		0.39
MutPred		0.51		Loss of glycosylation at P3563 (P = 0.0722);
MVP		0.41
MPC		0.19
ClinPred		0.91	D
GERP RS		0.55
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs866647249; hg19: chr3-52428542;