16-20737236-G-A

Variant names:

• chr16-20737236-G-A
• rs778649204
• NM_017736.5:c.706C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PVS1_Strong PM2 PP5 BS1_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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 3.12

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]

ACMG classification

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
THUMPD1	NM_017736.5	c.706C>T	p.Gln236*	stop_gained	Exon 4 of 4	ENST00000396083.7	NP_060206.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THUMPD1	ENST00000396083.7	c.706C>T	p.Gln236*	stop_gained	Exon 4 of 4	1	NM_017736.5	ENSP00000379392.2

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

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

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:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurodevelopmental disorder with speech delay and variable ocular anomalies Pathogenic:1 Uncertain:1

Aug 10, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 27, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Dec 01, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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

Dec 15, 2021

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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

Other links and lift over

dbSNP: rs778649204; hg19: chr16-20748558;