chr3-52396682-G-C

Variant names:

• chr3-52396682-G-C
• rs365048
• NM_015512.5:c.11495G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015512.5(DNAH1):​c.11495G>C​(p.Arg3832Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R3832C) has been classified as Benign.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.65

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.11495G>C	p.Arg3832Pro	missense_variant	Exon 72 of 78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.11564G>C	p.Arg3855Pro	missense_variant	Exon 74 of 80		XP_016861618.1
DNAH1	XM_017006130.2	c.11495G>C	p.Arg3832Pro	missense_variant	Exon 73 of 79		XP_016861619.1
DNAH1	XM_017006131.2	c.11438G>C	p.Arg3813Pro	missense_variant	Exon 73 of 79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.11495G>C	p.Arg3832Pro	missense_variant	Exon 72 of 78	1	NM_015512.5	ENSP00000401514.2
DNAH1	ENST00000486752.5	n.11952G>C		non_coding_transcript_exon_variant	Exon 71 of 77	2
DNAH1	ENST00000488988.5	n.3281G>C		non_coding_transcript_exon_variant	Exon 19 of 25	2
DNAH1	ENST00000490713.5	n.2195G>C		non_coding_transcript_exon_variant	Exon 15 of 20	5		ENSP00000419071.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74302

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_noAF	Benign	-0.68
CADD	Pathogenic	29
LIST_S2	Uncertain	0.93	D
MetaRNN	Pathogenic	0.85	D
Sift4G	Uncertain	0.0020	D
Vest4		0.81
gMVP		0.94

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: rs365048; hg19: chr3-52430698;