2-218282104-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022152.6(TMBIM1):c.38G>A(p.Arg13His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,555,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000093 (0 hom.)
• Consequence: TMBIM1 NM_022152.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.206

Genes affected

TMBIM1 (HGNC:23410): (transmembrane BAX inhibitor motif containing 1) Enables death receptor binding activity. Involved in negative regulation of Fas signaling pathway; negative regulation of extrinsic apoptotic signaling pathway via death domain receptors; and negative regulation of protein localization to plasma membrane. Located in Golgi apparatus; endosome membrane; and lysosomal membrane. [provided by Alliance of Genome Resources, Apr 2022]

PNKD (HGNC:9153): (PNKD metallo-beta-lactamase domain containing) This gene is thought to play a role in the regulation of myofibrillogenesis. Mutations in this gene have been associated with the movement disorder paroxysmal non-kinesigenic dyskinesia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06221676).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMBIM1	NM_022152.6	c.38G>A	p.Arg13His	missense_variant	2/12	ENST00000258412.8
PNKD	NM_015488.5	c.236+10555C>T		intron_variant		ENST00000273077.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMBIM1	ENST00000258412.8	c.38G>A	p.Arg13His	missense_variant	2/12	1	NM_022152.6	P1
PNKD	ENST00000273077.9	c.236+10555C>T		intron_variant		1	NM_015488.5

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152086 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000515 AC: 1 AN: 194318 Hom.: 0 AF XY: 0.00000942 AC XY: 1 AN XY: 106116

Gnomad AFR exome AF: 0.0000725

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000926 AC: 13 AN: 1403176 Hom.: 0 Cov.: 37 AF XY: 0.00000865 AC XY: 6 AN XY: 693614

Gnomad4 AFR exome AF: 0.0000321

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000127

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.00000830

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74428

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 07, 2022

The c.38G>A (p.R13H) alteration is located in exon 2 (coding exon 1) of the TMBIM1 gene. This alteration results from a G to A substitution at nucleotide position 38, causing the arginine (R) at amino acid position 13 to be replaced by a histidine (H). 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	Benign	0.25
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	21
Dann	Benign	0.93
DEOGEN2	Benign	0.0033	T;T;T;.;.;.;T;T;T;T;.;T;.;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.60	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.062	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L;L;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.54	N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.29
Sift	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;.;.
Sift4G	Benign	0.20	T;T;T;T;.;.;.;.;.;T;T;T;.;T
Polyphen		0.0020	B;B;B;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.22
MVP		0.31
MPC		0.18
ClinPred		0.040	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.053
gMVP		0.21

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: rs767796792; hg19: chr2-219146827;