NM_001195528.2:c.355A>G

Variant names:

• chr11-75241404-A-G
• rs1380505977
• NM_001195528.2:c.355A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001195528.2(TPBGL):​c.355A>G​(p.Ser119Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000827 in 1,209,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S119C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: TPBGL NM_001195528.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0560
• Publications: 0 publications found

Genes affected

TPBGL (HGNC:44159): (trophoblast glycoprotein like) Predicted to be involved in negative regulation of canonical Wnt signaling pathway. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000308808 (HGNC:):

TPBGL-AS1 (HGNC:55506): (TPBGL antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10247356).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195528.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPBGL	NM_001195528.2	MANE Select	c.355A>G	p.Ser119Gly	missense	Exon 1 of 1	NP_001182457.1	P0DKB5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPBGL	ENST00000562197.3	TSL:6 MANE Select	c.355A>G	p.Ser119Gly	missense	Exon 1 of 1	ENSP00000474988.1	P0DKB5
	ENSG00000308808	ENST00000836519.1		n.175+1139T>C		intron	N/A
	TPBGL-AS1	ENST00000530792.1	TSL:3	n.-231T>C		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.27e-7 AC: 1 AN: 1209848 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 592634

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23878

American (AMR) AF: 0.0000711 AC: 1 AN: 14066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18724

East Asian (EAS) AF: 0.00 AC: 0 AN: 25832

South Asian (SAS) AF: 0.00 AC: 0 AN: 56120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3574

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 989892

Other (OTH) AF: 0.00 AC: 0 AN: 48504

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	21
DANN	Benign	0.48
DEOGEN2	Benign	0.016	T
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.28	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.10	T
MutationAssessor	Benign	0.77	N
PhyloP100		-0.056
PrimateAI	Pathogenic	0.89	D
Sift4G	Benign	0.54	T
Vest4		0.062
MVP		0.43
GERP RS		0.54
Varity_R		0.18
gMVP		0.13
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs1380505977; hg19: chr11-74952449;