rs1077989

Variant names:

• chr14-67509105-A-C
• rs1077989
• NM_001348544.2:c.-256-5554T>G

Variant summary

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

The NM_001348544.2(TMEM229B):​c.-256-5554T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 151,852 control chromosomes in the GnomAD database, including 13,578 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 0.40 (13578 hom., cov: 30)
• Consequence: TMEM229B NM_001348544.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.408
• Publications: 38 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=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM229B	NM_001348544.2	c.-256-5554T>G		intron_variant	Intron 1 of 3		NP_001335473.1
TMEM229B	NM_001348546.2	c.-191-21933T>G		intron_variant	Intron 1 of 2		NP_001335475.1
TMEM229B	NM_001348547.2	c.-191-21933T>G		intron_variant	Intron 1 of 2		NP_001335476.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM229B	ENST00000357461.7	c.-192+5981T>G		intron_variant	Intron 1 of 2	2		ENSP00000350050.2
TMEM229B	ENST00000554278.6	c.-191-21933T>G		intron_variant	Intron 1 of 2	4		ENSP00000452402.2
TMEM229B	ENST00000555994.6	c.-256-5554T>G		intron_variant	Intron 1 of 3	3		ENSP00000452144.2

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60270 AN: 151732 Hom.: 13570 Cov.: 30

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.522

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.442

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.452

Gnomad MID AF: 0.564

Gnomad NFE AF: 0.480

Gnomad OTH AF: 0.406

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

GnomAD4 genome AF: 0.397 AC: 60283 AN: 151852 Hom.: 13578 Cov.: 30 AF XY: 0.404 AC XY: 29953 AN XY: 74204

African (AFR) AF: 0.170 AC: 7062 AN: 41450

American (AMR) AF: 0.522 AC: 7965 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.507 AC: 1758 AN: 3468

East Asian (EAS) AF: 0.441 AC: 2270 AN: 5142

South Asian (SAS) AF: 0.537 AC: 2581 AN: 4810

European-Finnish (FIN) AF: 0.452 AC: 4751 AN: 10522

Middle Eastern (MID) AF: 0.558 AC: 163 AN: 292

European-Non Finnish (NFE) AF: 0.480 AC: 32572 AN: 67896

Other (OTH) AF: 0.409 AC: 862 AN: 2110

Alfa AF: 0.463 Hom.: 76919

Bravo AF: 0.391

Asia WGS AF: 0.458 AC: 1594 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.7
DANN	Benign	0.63
PhyloP100		0.41
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: rs1077989; hg19: chr14-67975822;