1-1426200-C-T

Position:

• chr1-1426200-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001146685.2(TMEM88B):​c.73C>T​(p.Pro25Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMEM88B NM_001146685.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.02

Genes affected

TMEM88B (HGNC:37099): (transmembrane protein 88B) Predicted to enable PDZ domain binding activity. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM88B	NM_001146685.2	c.73C>T	p.Pro25Ser	missense_variant	1/2	ENST00000378821.4	NP_001140157.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM88B	ENST00000378821.4	c.73C>T	p.Pro25Ser	missense_variant	1/2	2	NM_001146685.2	ENSP00000455099	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1263170 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 613968

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Feb 17, 2022

The c.73C>T (p.P25S) alteration is located in exon 1 (coding exon 1) of the TMEM88B gene. This alteration results from a C to T substitution at nucleotide position 73, causing the proline (P) at amino acid position 25 to be replaced by a serine (S). 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	0.30
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.46	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	0.95	N
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.8	D
Sift	Benign	0.048	D
Sift4G	Benign	0.34	T
Polyphen		0.94	P
Vest4		0.42
MVP		0.64
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.15
gMVP		0.40

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: rs1570106437; hg19: chr1-1361580;