16-20737894-G-A

Position:

• chr16-20737894-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_017736.5(THUMPD1):​c.469C>T​(p.Arg157Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,484 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 Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: THUMPD1 NM_017736.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.88

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 8 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 16-20737894-G-A is Pathogenic according to our data. Variant chr16-20737894-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1333099.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-20737894-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THUMPD1	NM_017736.5	c.469C>T	p.Arg157Ter	stop_gained	3/4	ENST00000396083.7	NP_060206.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THUMPD1	ENST00000396083.7	c.469C>T	p.Arg157Ter	stop_gained	3/4	1	NM_017736.5	ENSP00000379392	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461484 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727060

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 15, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.90	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.41
GERP RS		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr16-20749216; COSMIC: COSV67263624; COSMIC: COSV67263624;