19-35546537-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 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.

• 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a chain BOS complex subunit TMEM147 (size 223) in uniprot entity TM147_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_032635.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM147	NM_032635.4	c.159G>C	p.Leu53Phe	missense_variant	Exon 3 of 7	ENST00000222284.10	NP_116024.1
TMEM147	NM_001242597.2	c.12G>C	p.Leu4Phe	missense_variant	Exon 2 of 6		NP_001229526.1
TMEM147	NM_001242598.2	c.159G>C	p.Leu53Phe	missense_variant	Exon 3 of 5		NP_001229527.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM147	ENST00000222284.10	c.159G>C	p.Leu53Phe	missense_variant	Exon 3 of 7	1	NM_032635.4	ENSP00000222284.4

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

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;D;D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.2	M;.;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.050	T;D;T
Polyphen		1.0	D;.;.
Vest4		0.70
MutPred		0.80		Gain of methylation at K49 (P = 0.0787);.;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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-36037439;