16-20737728-T-TC

Variant names:

• chr16-20737728-T-TC
• NM_017736.5:c.634dupG

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_017736.5(THUMPD1):​c.634dupG​(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
• Publications: 0 publications found

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

Our verdict: Pathogenic. The variant received 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. Fraction of 0.403 CDS is truncated, and there are 3 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 VariationId is 1333102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017736.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THUMPD1	NM_017736.5	MANE Select	c.634dupG	p.Glu212GlyfsTer18	frameshift	Exon 3 of 4	NP_060206.2
	THUMPD1	NM_001304550.2		c.634dupG	p.Glu212GlyfsTer18	frameshift	Exon 3 of 5	NP_001291479.1	Q9NXG2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THUMPD1	ENST00000396083.7	TSL:1 MANE Select	c.634dupG	p.Glu212GlyfsTer18	frameshift	Exon 3 of 4	ENSP00000379392.2	Q9NXG2
	THUMPD1	ENST00000381337.6	TSL:1	c.634dupG	p.Glu212GlyfsTer18	frameshift	Exon 3 of 5	ENSP00000370741.2	Q9NXG2
	THUMPD1	ENST00000888379.1		c.634dupG	p.Glu212GlyfsTer18	frameshift	Exon 3 of 5	ENSP00000558438.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Neurodevelopmental disorder with speech delay and variable ocular anomalies (2)
1	-	-	Neurodevelopmental disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.6

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

Other links and lift over

hg19: chr16-20749050;