chr19-35545758-G-C

Position:

• chr19-35545758-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PS1_Moderate PM1 PM2 PP5 BP4

The NM_032635.4(TMEM147):​c.19G>C​(p.Gly7Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000713 in 1,612,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: TMEM147 NM_032635.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 5.56

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

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PS1: Transcript NM_032635.4 (TMEM147) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a chain BOS complex subunit TMEM147 (size 223) in uniprot entity TM147_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_032635.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-35545758-G-C is Pathogenic according to our data. Variant chr19-35545758-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1711115.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=1, Uncertain_significance=1}. Variant chr19-35545758-G-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.2533117). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM147	NM_032635.4	c.19G>C	p.Gly7Arg	missense_variant	1/7	ENST00000222284.10
TMEM147-AS1	NR_038396.1	n.93+179C>G		intron_variant, non_coding_transcript_variant
TMEM147	NM_001242598.2	c.19G>C	p.Gly7Arg	missense_variant	1/5
TMEM147	NM_001242597.2	c.-200G>C		5_prime_UTR_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM147	ENST00000222284.10	c.19G>C	p.Gly7Arg	missense_variant	1/7	1	NM_032635.4	P1
TMEM147-AS1	ENST00000589137.5	n.93+179C>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.0000484 AC: 12 AN: 247848 Hom.: 0 AF XY: 0.0000521 AC XY: 7 AN XY: 134404

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000541

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000630 AC: 92 AN: 1460634 Hom.: 0 Cov.: 31 AF XY: 0.0000674 AC XY: 49 AN XY: 726696

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000630

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.000174 AC XY: 13 AN XY: 74500

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000242

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurodevelopmental disorder with facial dysmorphism, absent language, and pseudo-pelger-huet anomaly Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	-	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 04, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects TMEM147 function (PMID: 36044892). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1711115). This missense change has been observed in individuals with clinical features of TMEM147-related neurodevelopmental disorder (PMID: 36044892). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs200901862, gnomAD 0.01%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 7 of the TMEM147 protein (p.Gly7Arg). -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 2023

The c.19G>C (p.G7R) alteration is located in exon 1 (coding exon 1) of the TMEM147 gene. This alteration results from a G to C substitution at nucleotide position 19, causing the glycine (G) at amino acid position 7 to be replaced by an arginine (R). Based on data from gnomAD, the C allele has an overall frequency of 0.005% (14/279204) total alleles studied. The highest observed frequency was 0.014% (5/35396) of Latino alleles. This variant has been reported to be homozygous in three individuals from two families with features consistent with TMEM147-related neurodevelopmental disorder (Thomas, 2022). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	T;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Uncertain	0.34
Sift	Benign	0.034	D;T
Sift4G	Uncertain	0.049	D;T
Polyphen		1.0	D;.
Vest4		0.55
MutPred		0.62		Gain of methylation at G7 (P = 0.0054);Gain of methylation at G7 (P = 0.0054);
MVP		0.19
MPC		1.2
ClinPred		0.94	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs200901862; hg19: chr19-36036660;