19-35546998-T-A

Position:

• chr19-35546998-T-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_Moderate PM1 PM2 PP3_Moderate PP5_Moderate

The NM_032635.4(TMEM147):​c.398T>A​(p.Ile133Asn) variant causes a missense change. 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMEM147 NM_032635.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.99

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 Pathogenic. Variant got 10 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.935
• PP5: Variant 19-35546998-T-A is Pathogenic according to our data. Variant chr19-35546998-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 1708022.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-35546998-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMEM147	NM_032635.4	c.398T>A	p.Ile133Asn	missense_variant	5/7	ENST00000222284.10
TMEM147	NM_001242597.2	c.251T>A	p.Ile84Asn	missense_variant	4/6
TMEM147	NM_001242598.2	c.208-121T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMEM147	ENST00000222284.10	c.398T>A	p.Ile133Asn	missense_variant	5/7	1	NM_032635.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

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	Oct 28, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.98	D;.;.
Vest4		0.95
MutPred		0.81		Gain of sheet (P = 0.0477);.;Gain of sheet (P = 0.0477);
MVP		0.68
MPC		1.5
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-36037900;