rs766117149

chr3-52349256-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_015512.5(DNAH1):c.2362C>T(p.Arg788Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,613,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: DNAH1 NM_015512.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.111

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040347427).
• BP6: Variant 3-52349256-C-T is Benign according to our data. Variant chr3-52349256-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 478428.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH1	NM_015512.5	c.2362C>T	p.Arg788Trp	missense_variant	14/78	ENST00000420323.7
DNAH1	XM_017006129.2	c.2362C>T	p.Arg788Trp	missense_variant	15/80
DNAH1	XM_017006130.2	c.2362C>T	p.Arg788Trp	missense_variant	15/79
DNAH1	XM_017006131.2	c.2362C>T	p.Arg788Trp	missense_variant	15/79

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH1	ENST00000420323.7	c.2362C>T	p.Arg788Trp	missense_variant	14/78	1	NM_015512.5	P1
DNAH1	ENST00000486752.5	n.2623C>T		non_coding_transcript_exon_variant	14/77	2
DNAH1	ENST00000497875.1	n.2527C>T		non_coding_transcript_exon_variant	15/21	2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

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

GnomAD3 exomes AF: 0.0000844 AC: 21 AN: 248916 Hom.: 0 AF XY: 0.0000666 AC XY: 9 AN XY: 135070

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00100

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000335 AC: 49 AN: 1461604 Hom.: 0 Cov.: 34 AF XY: 0.0000330 AC XY: 24 AN XY: 727082

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152156 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74322

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000277 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2022

The c.2362C>T (p.R788W) alteration is located in exon 14 (coding exon 13) of the DNAH1 gene. This alteration results from a C to T substitution at nucleotide position 2362, causing the arginine (R) at amino acid position 788 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	18
Dann	Uncertain	0.98
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.049
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.030	D
Vest4		0.21
MutPred		0.69		Loss of solvent accessibility (P = 0.0299);
MVP		0.092
MPC		0.13
ClinPred		0.029	T
GERP RS		-0.31
gMVP		0.38

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: rs766117149; hg19: chr3-52383272; COSMIC: COSV70230246;