19-35545908-GGAAATGCGTCCAGGCTGGA-G

Variant names:

• chr19-35545908-GGAAATGCGTCCAGGCTGGA-G
• rs1235530554
• NM_032635.4:c.100_118delAAATGCGTCCAGGCTGGAG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_032635.4(TMEM147):​c.100_118delAAATGCGTCCAGGCTGGAG​(p.Lys34SerfsTer33) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM147 NM_032635.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.73
• Publications: 1 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-AS1 (HGNC:51273): (TMEM147 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 19-35545908-GGAAATGCGTCCAGGCTGGA-G is Pathogenic according to our data. Variant chr19-35545908-GGAAATGCGTCCAGGCTGGA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1708019.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.100_118delAAATGCGTCCAGGCTGGAG	p.Lys34SerfsTer33	frameshift	Exon 2 of 7	NP_116024.1	Q9BVK8-1
	TMEM147	NM_001242598.2		c.100_118delAAATGCGTCCAGGCTGGAG	p.Lys34SerfsTer42	frameshift	Exon 2 of 5	NP_001229527.1
	TMEM147	NM_001242597.2		c.-48_-30delAAATGCGTCCAGGCTGGAG		5_prime_UTR	Exon 1 of 6	NP_001229526.1	Q9BVK8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM147	ENST00000222284.10	TSL:1 MANE Select	c.100_118delAAATGCGTCCAGGCTGGAG	p.Lys34SerfsTer33	frameshift	Exon 2 of 7	ENSP00000222284.4	Q9BVK8-1
	TMEM147-AS1	ENST00000589137.5	TSL:1	n.93+10_93+28delTCCAGCCTGGACGCATTTC		intron	N/A
	TMEM147	ENST00000928931.1		c.100_118delAAATGCGTCCAGGCTGGAG	p.Lys34SerfsTer39	frameshift	Exon 2 of 7	ENSP00000598990.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250688 AF XY: 0.00000737

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

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
PhyloP100		8.7
Mutation Taster		=29/171	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1235530554; hg19: chr19-36036810;