14-67473571-A-G

Variant names:

• chr14-67473571-A-G
• rs1768252268
• NM_001348543.2:c.353T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001348543.2(TMEM229B):​c.353T>C​(p.Leu118Pro) variant causes a missense change involving the alteration of a conserved nucleotide. 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 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: 7.38
• Publications: 0 publications found

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]

GPHN Gene-Disease associations (from GenCC):

• sulfite oxidase deficiency due to molybdenum cofactor deficiency type C

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary hyperekplexia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.826

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001348543.2. 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
	TMEM229B	NM_001348543.2	MANE Select	c.353T>C	p.Leu118Pro	missense	Exon 3 of 3	NP_001335472.1	Q8NBD8
	TMEM229B	NM_001348541.2		c.485T>C	p.Leu162Pro	missense	Exon 3 of 3	NP_001335470.1
	TMEM229B	NM_001348542.2		c.353T>C	p.Leu118Pro	missense	Exon 3 of 3	NP_001335471.1	Q8NBD8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM229B	ENST00000554480.6	TSL:2 MANE Select	c.353T>C	p.Leu118Pro	missense	Exon 3 of 3	ENSP00000450859.2	Q8NBD8
	TMEM229B	ENST00000357461.7	TSL:2	c.353T>C	p.Leu118Pro	missense	Exon 3 of 3	ENSP00000350050.2	Q8NBD8
	TMEM229B	ENST00000554278.6	TSL:4	c.353T>C	p.Leu118Pro	missense	Exon 3 of 3	ENSP00000452402.2	Q8NBD8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.033	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.4
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.83
MutPred		0.52		Gain of catalytic residue at T117 (P = 0)
MVP		0.19
MPC		2.5
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.95
gMVP		0.99
Mutation Taster		=38/62	disease causing

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: rs1768252268; hg19: chr14-67940288;