chr17-78424052-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP3_ModerateBS1_Supporting
The NM_173628.4(DNAH17):c.13243C>T(p.Arg4415Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000452 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00034 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00046 ( 0 hom. )
Consequence
DNAH17
NM_173628.4 missense
NM_173628.4 missense
Scores
4
3
6
Clinical Significance
Conservation
PhyloP100: 1.67
Genes affected
DNAH17 (HGNC:2946): (dynein axonemal heavy chain 17) Dyneins are microtubule-associated motor protein complexes composed of several heavy, light, and intermediate chains. DNAH17 is a heavy chain associated with axonemal dynein (Milisav and Affara, 1998 [PubMed 9545504]).[supplied by OMIM, Mar 2008]
PGS1 (HGNC:30029): (phosphatidylglycerophosphate synthase 1) Predicted to enable CDP-diacylglycerol-glycerol-3-phosphate 3-phosphatidyltransferase activity and calcium ion binding activity. Predicted to be involved in cardiolipin biosynthetic process and diacylglycerol metabolic process. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
BS1
?
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000341 (52/152340) while in subpopulation SAS AF= 0.000621 (3/4828). AF 95% confidence interval is 0.000317. There are 0 homozygotes in gnomad4. There are 27 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAH17 | NM_173628.4 | c.13243C>T | p.Arg4415Cys | missense_variant | 81/81 | ENST00000389840.7 | |
PGS1 | NM_024419.5 | c.*11-9G>A | splice_polypyrimidine_tract_variant, intron_variant | ENST00000262764.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAH17 | ENST00000389840.7 | c.13243C>T | p.Arg4415Cys | missense_variant | 81/81 | 5 | NM_173628.4 | P1 | |
PGS1 | ENST00000262764.11 | c.*11-9G>A | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_024419.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000342 AC: 52AN: 152222Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000353 AC: 88AN: 249486Hom.: 0 AF XY: 0.000407 AC XY: 55AN XY: 135002
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GnomAD4 exome AF: 0.000463 AC: 677AN: 1461706Hom.: 0 Cov.: 31 AF XY: 0.000474 AC XY: 345AN XY: 727134
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 18, 2021 | The c.13243C>T (p.R4415C) alteration is located in exon 81 (coding exon 80) of the DNAH17 gene. This alteration results from a C to T substitution at nucleotide position 13243, causing the arginine (R) at amino acid position 4415 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
Vest4
MVP
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 2
DS_AL_spliceai
Position offset: 9
Find out detailed SpliceAI scores and Pangolin per-transcript scores at