14-67512996-G-A

Variant names:

• chr14-67512996-G-A
• rs7156144
• NM_001348544.2:c.-257+2090C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001348544.2(TMEM229B):​c.-257+2090C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 151,986 control chromosomes in the GnomAD database, including 10,137 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.35 (10137 hom., cov: 32)
• Consequence: TMEM229B NM_001348544.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.502
• Publications: 16 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen
• hereditary hyperekplexia

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

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001348544.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM229B	NM_001348544.2		c.-257+2090C>T		intron	N/A	NP_001335473.1
	TMEM229B	NM_001348546.2		c.-192+20766C>T		intron	N/A	NP_001335475.1
	TMEM229B	NM_001348547.2		c.-192+20640C>T		intron	N/A	NP_001335476.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM229B	ENST00000357461.7	TSL:2	c.-192+2090C>T		intron	N/A	ENSP00000350050.2
	TMEM229B	ENST00000554278.6	TSL:4	c.-192+20640C>T		intron	N/A	ENSP00000452402.2
	TMEM229B	ENST00000555994.6	TSL:3	c.-257+2090C>T		intron	N/A	ENSP00000452144.2

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53063 AN: 151868 Hom.: 10133 Cov.: 32

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.427

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.430

Gnomad SAS AF: 0.389

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.334

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.349 AC: 53068 AN: 151986 Hom.: 10137 Cov.: 32 AF XY: 0.352 AC XY: 26163 AN XY: 74294

African (AFR) AF: 0.178 AC: 7370 AN: 41432

American (AMR) AF: 0.427 AC: 6527 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 1502 AN: 3470

East Asian (EAS) AF: 0.429 AC: 2228 AN: 5188

South Asian (SAS) AF: 0.389 AC: 1873 AN: 4814

European-Finnish (FIN) AF: 0.366 AC: 3860 AN: 10536

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.421 AC: 28597 AN: 67956

Other (OTH) AF: 0.330 AC: 696 AN: 2108

Alfa AF: 0.399 Hom.: 18346

Bravo AF: 0.345

Asia WGS AF: 0.355 AC: 1237 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.6
DANN	Benign	0.37
PhyloP100		-0.50
Mutation Taster		=100/0	polymorphism (auto)

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: rs7156144; hg19: chr14-67979713;