14-67473620-G-A

Variant names:

• chr14-67473620-G-A
• NM_001348543.2:c.304C>T

Variant summary

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

The NM_001348543.2(TMEM229B):​c.304C>T​(p.Pro102Ser) variant causes a missense change involving the alteration of a 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: 33)
• Consequence: TMEM229B NM_001348543.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.19

Genes affected

TMEM229B (HGNC:20130): (transmembrane protein 229B) Predicted to act upstream of or within response to bacterium. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

GPHN (HGNC:15465): (gephyrin) This gene encodes a neuronal assembly protein that anchors inhibitory neurotransmitter receptors to the postsynaptic cytoskeleton via high affinity binding to a receptor subunit domain and tubulin dimers. In nonneuronal tissues, the encoded protein is also required for molybdenum cofactor biosynthesis. Mutations in this gene may be associated with the neurological condition hyperplexia and also lead to molybdenum cofactor deficiency. Numerous alternatively spliced transcript variants encoding different isoforms have been described; however, the full-length nature of all transcript variants is not currently known. [provided by RefSeq, Jul 2008]

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 rank	MANE	Protein	UniProt
TMEM229B	NM_001348543.2	c.304C>T	p.Pro102Ser	missense_variant	Exon 3 of 3	ENST00000554480.6	NP_001335472.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM229B	ENST00000554480.6	c.304C>T	p.Pro102Ser	missense_variant	Exon 3 of 3	2	NM_001348543.2	ENSP00000450859.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.304C>T (p.P102S) alteration is located in exon 3 (coding exon 1) of the TMEM229B gene. This alteration results from a C to T substitution at nucleotide position 304, causing the proline (P) at amino acid position 102 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;.;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.66	D;D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.9	L;L;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Uncertain	0.46
Sift	Benign	0.34	T;T;T
Sift4G	Benign	0.16	T;T;.
Polyphen		1.0	D;D;.
Vest4		0.45
MutPred		0.55		Gain of catalytic residue at Q107 (P = 2e-04);Gain of catalytic residue at Q107 (P = 2e-04);Gain of catalytic residue at Q107 (P = 2e-04);
MVP		0.15
MPC		2.0
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.21
gMVP		0.96

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: chr14-67940337; COSMIC: COSV100664270; COSMIC: COSV100664270;