19-35546990-G-A

Variant names:

• chr19-35546990-G-A
• NM_032635.4:c.390G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_032635.4(TMEM147):​c.390G>A​(p.Trp130*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM147 NM_032635.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.71
• Publications: 0 publications found

Genes affected

TMEM147 (HGNC:30414): (transmembrane protein 147) Enables ribosome binding activity. Located in endoplasmic reticulum membrane. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

TMEM147 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with facial dysmorphism, absent language, and pseudo-pelger-huet anomaly

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• complex neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-35546990-G-A is Pathogenic according to our data. Variant chr19-35546990-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1708025.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032635.4. 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
	TMEM147	NM_032635.4	MANE Select	c.390G>A	p.Trp130*	stop_gained	Exon 5 of 7	NP_116024.1	Q9BVK8-1
	TMEM147	NM_001242597.2		c.243G>A	p.Trp81*	stop_gained	Exon 4 of 6	NP_001229526.1	Q9BVK8-2
	TMEM147	NM_001242598.2		c.208-129G>A		intron	N/A	NP_001229527.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM147	ENST00000222284.10	TSL:1 MANE Select	c.390G>A	p.Trp130*	stop_gained	Exon 5 of 7	ENSP00000222284.4	Q9BVK8-1
	TMEM147	ENST00000928931.1		c.408G>A	p.Trp136*	stop_gained	Exon 5 of 7	ENSP00000598990.1
	TMEM147	ENST00000928929.1		c.387G>A	p.Trp129*	stop_gained	Exon 5 of 7	ENSP00000598988.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodevelopmental disorder with facial dysmorphism, absent language, and pseudo-pelger-huet anomaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		8.7
Vest4		0.41
GERP RS		5.1
Mutation Taster		=22/178	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: chr19-36037892;