16-20737728-T-TC

Position:

• chr16-20737728-T-TC

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_017736.5(THUMPD1):​c.634_635insG​(p.Glu212GlyfsTer18) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: THUMPD1 NM_017736.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.64

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-20737728-T-TC is Pathogenic according to our data. Variant chr16-20737728-T-TC is described in ClinVar as [Pathogenic]. Clinvar id is 1333102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THUMPD1	NM_017736.5	c.634_635insG	p.Glu212GlyfsTer18	frameshift_variant	3/4	ENST00000396083.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THUMPD1	ENST00000396083.7	c.634_635insG	p.Glu212GlyfsTer18	frameshift_variant	3/4	1	NM_017736.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with speech delay and variable ocular anomalies Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 10, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 21, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurodevelopmental disorder with speech delay and variable ocular anomalies (MIM#619989). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0252 - This variant is homozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is expected to disrupt the THUMP domain (DECIPHER). (I) 0704 - Another premature termination variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Gln236*) has been reported as homozygous in three individuals with syndromic neurodevelopmental disorder in two families (PMID: 35196516). It has also been reported as a VUS by a clinical testing laboratory, however no further information was provided (ClinVar). In addition, p.(Leu258del) has been reported in three affected siblings with syndromic neurodevelopmental disorder (PMID: 35196516). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by research trio analysis, PMID: 35196516). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Neurodevelopmental disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

research

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

Dec 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-20749050;