chr14-67472766-T-C

Variant names:

• chr14-67472766-T-C
• rs17104363
• NM_001348543.2:c.*654A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001348543.2(TMEM229B):​c.*654A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 152,734 control chromosomes in the GnomAD database, including 1,016 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 0.11 (1007 hom., cov: 32)
  • Exomes 𝑓: 0.12 (9 hom.)
• Consequence: TMEM229B NM_001348543.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.11
• Publications: 15 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM229B	NM_001348543.2	c.*654A>G		3_prime_UTR_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.*654A>G		3_prime_UTR_variant	Exon 3 of 3	2	NM_001348543.2	ENSP00000450859.2

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17078 AN: 151440 Hom.: 1005 Cov.: 32

Gnomad AFR AF: 0.0899

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.0885

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.123

GnomAD4 exome AF: 0.116 AC: 136 AN: 1174 Hom.: 9 Cov.: 0 AF XY: 0.129 AC XY: 87 AN XY: 676

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.0682 AC: 3 AN: 44

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 1 AN: 6

East Asian (EAS) AF: 0.167 AC: 1 AN: 6

South Asian (SAS) AF: 0.0833 AC: 1 AN: 12

European-Finnish (FIN) AF: 0.102 AC: 50 AN: 490

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.130 AC: 73 AN: 560

Other (OTH) AF: 0.135 AC: 7 AN: 52

GnomAD4 genome AF: 0.113 AC: 17088 AN: 151560 Hom.: 1007 Cov.: 32 AF XY: 0.114 AC XY: 8429 AN XY: 74086

African (AFR) AF: 0.0899 AC: 3696 AN: 41104

American (AMR) AF: 0.0883 AC: 1346 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 471 AN: 3422

East Asian (EAS) AF: 0.133 AC: 686 AN: 5158

South Asian (SAS) AF: 0.105 AC: 507 AN: 4806

European-Finnish (FIN) AF: 0.114 AC: 1209 AN: 10602

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.128 AC: 8680 AN: 67926

Other (OTH) AF: 0.123 AC: 258 AN: 2096

Alfa AF: 0.120 Hom.: 3466

Bravo AF: 0.110

Asia WGS AF: 0.100 AC: 349 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	14
DANN	Benign	0.83
PhyloP100		2.1
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: rs17104363; hg19: chr14-67939483;