19-35546537-G-C

Variant names:

• chr19-35546537-G-C
• rs746637173
• NM_032635.4:c.159G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_032635.4(TMEM147):​c.159G>C​(p.Leu53Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMEM147 NM_032635.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0960
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.48534 (below the threshold of 3.09). Trascript score misZ: 0.93164 (below the threshold of 3.09). GenCC associations: The gene is linked to complex neurodevelopmental disorder, neurodevelopmental disorder with facial dysmorphism, absent language, and pseudo-pelger-huet anomaly.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761

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.159G>C	p.Leu53Phe	missense	Exon 3 of 7	NP_116024.1	Q9BVK8-1
	TMEM147	NM_001242597.2		c.12G>C	p.Leu4Phe	missense	Exon 2 of 6	NP_001229526.1	Q9BVK8-2
	TMEM147	NM_001242598.2		c.159G>C	p.Leu53Phe	missense	Exon 3 of 5	NP_001229527.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM147	ENST00000222284.10	TSL:1 MANE Select	c.159G>C	p.Leu53Phe	missense	Exon 3 of 7	ENSP00000222284.4	Q9BVK8-1
	TMEM147	ENST00000928931.1		c.159G>C	p.Leu53Phe	missense	Exon 3 of 7	ENSP00000598990.1
	TMEM147	ENST00000928929.1		c.159G>C	p.Leu53Phe	missense	Exon 3 of 7	ENSP00000598988.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460800 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726624

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86036

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111522

Other (OTH) AF: 0.00 AC: 0 AN: 60332

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-0.096
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.050	T
Polyphen		1.0	D
Vest4		0.70
MutPred		0.80		Gain of methylation at K49 (P = 0.0787)
MVP		0.31
MPC		1.2
ClinPred		0.99	D
GERP RS		-0.80
Varity_R		0.34
gMVP		0.86
Mutation Taster		=45/55	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

dbSNP: rs746637173; hg19: chr19-36037439;