16-20737236-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PVS1_StrongPM2PP5BS1_Supporting

The NM_017736.5(THUMPD1):​c.706C>T​(p.Gln236*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

THUMPD1
NM_017736.5 stop_gained

Scores

3
3
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 3.12
Variant links:
Genes affected
THUMPD1 (HGNC:23807): (THUMP domain containing 1) Enables RNA binding activity. Predicted to be involved in tRNA modification. Predicted to be located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]
ACSM3 (HGNC:10522): (acyl-CoA synthetase medium chain family member 3) Enables butyrate-CoA ligase activity. Predicted to be involved in acyl-CoA metabolic process and fatty acid biosynthetic process. Located in mitochondrion. Implicated in IgA glomerulonephritis. Biomarker of ulcerative colitis. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.335 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-20737236-G-A is Pathogenic according to our data. Variant chr16-20737236-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1333096.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}. Variant chr16-20737236-G-A is described in Lovd as [Likely_pathogenic]. Variant chr16-20737236-G-A is described in Lovd as [Pathogenic].
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000116 (17/1461786) while in subpopulation SAS AF= 0.000197 (17/86252). AF 95% confidence interval is 0.000125. There are 0 homozygotes in gnomad4_exome. There are 12 alleles in male gnomad4_exome subpopulation. Median coverage is 31. 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 rank MANE Protein UniProt
THUMPD1NM_017736.5 linkc.706C>T p.Gln236* stop_gained Exon 4 of 4 ENST00000396083.7 NP_060206.2 Q9NXG2A0A024R388Q6MZT3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
THUMPD1ENST00000396083.7 linkc.706C>T p.Gln236* stop_gained Exon 4 of 4 1 NM_017736.5 ENSP00000379392.2 Q9NXG2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000200
AC:
5
AN:
250234
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135368
show subpopulations
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:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1461786
Hom.:
0
Cov.:
31
AF XY:
0.0000165
AC XY:
12
AN XY:
727196
show subpopulations
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:
0.000197
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Neurodevelopmental disorder with speech delay and variable ocular anomalies Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityJan 27, 2021- -
Pathogenic, no assertion criteria providedliterature onlyOMIMAug 10, 2022- -
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsDec 01, 2023The c.706C>T (p.Q236*) alteration, located in exon 4 (coding exon 4) of the THUMPD1 gene, consists of a C to T substitution at nucleotide position 706. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 236. This alteration occurs at the 3' terminus of the THUMPD1 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 33% of the protein. Premature stop codons are typically deleterious in nature and a significant portion of the protein is affected. Based on data from gnomAD, the T allele has an overall frequency of 0.002% (5/250234) total alleles studied. The highest observed frequency was 0.016% (5/30606) of South Asian alleles. This variant has been reported homozygous in multiple individuals with features consistent with THUMPD1-related neurodevelopmental disorder (Maddirevula, 2019; Broly, 2022). Based on the available evidence, this alteration is classified as likely pathogenic. -
Neurodevelopmental disorder Pathogenic:1
Pathogenic, criteria provided, single submitterresearchLaboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de NantesDec 15, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.34
D
BayesDel_noAF
Pathogenic
0.50
CADD
Pathogenic
37
DANN
Uncertain
0.99
Eigen
Pathogenic
0.82
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.90
D
Vest4
0.13
GERP RS
3.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs778649204; hg19: chr16-20748558; API