3-52357632-G-C

Variant names:

• chr3-52357632-G-C
• rs140883175
• NM_015512.5:c.3877G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015512.5(DNAH1):​c.3877G>C​(p.Asp1293His) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,448,516 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. D1293N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.91

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH1	NM_015512.5	c.3877G>C	p.Asp1293His	missense_variant	Exon 23 of 78	ENST00000420323.7	NP_056327.4
DNAH1	XM_017006129.2	c.3877G>C	p.Asp1293His	missense_variant	Exon 24 of 80		XP_016861618.1
DNAH1	XM_017006130.2	c.3877G>C	p.Asp1293His	missense_variant	Exon 24 of 79		XP_016861619.1
DNAH1	XM_017006131.2	c.3877G>C	p.Asp1293His	missense_variant	Exon 24 of 79		XP_016861620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH1	ENST00000420323.7	c.3877G>C	p.Asp1293His	missense_variant	Exon 23 of 78	1	NM_015512.5	ENSP00000401514.2
DNAH1	ENST00000486752.5	n.4138G>C		non_coding_transcript_exon_variant	Exon 23 of 77	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000438 AC: 1 AN: 228418 Hom.: 0 AF XY: 0.00000808 AC XY: 1 AN XY: 123706

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000980

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1448516 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 719300

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000746 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.56	T
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.035	D
Vest4		0.62
MutPred		0.64		Loss of catalytic residue at M1296 (P = 0.0359);
MVP		0.60
MPC		0.61
ClinPred		0.98	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140883175; hg19: chr3-52391648;