14-21103220-C-T

Variant names:

• chr14-21103220-C-T
• rs1039472796
• NM_001395467.1:c.616C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001395467.1(TMEM253):​c.616C>T​(p.Gln206*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TMEM253 NM_001395467.1 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.451
• Publications: 0 publications found

Genes affected

TMEM253 (HGNC:32545): (transmembrane protein 253) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ZNF219 (HGNC:13011): (zinc finger protein 219) This gene is a member of the Kruppel-like zinc finger gene family. The encoded protein functions as a transcriptional repressor of the high mobility group nucleosome binding domain 1 protein, which is associated with transcriptionally active chromatin. [provided by RefSeq, Apr 2017]

ZNF219 Gene-Disease associations (from GenCC):

• microphthalmia

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395467.1. 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
	TMEM253	NM_001395467.1	MANE Select	c.616C>T	p.Gln206*	stop_gained	Exon 7 of 7	NP_001382396.1	P0C7T8
	TMEM253	NM_001146683.2		c.616C>T	p.Gln206*	stop_gained	Exon 8 of 8	NP_001140155.1	P0C7T8
	TMEM253	NM_001395464.1		c.505C>T	p.Gln169*	stop_gained	Exon 7 of 7	NP_001382393.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM253	ENST00000556585.3	TSL:5 MANE Select	c.616C>T	p.Gln206*	stop_gained	Exon 7 of 7	ENSP00000451229.2	P0C7T8
	TMEM253	ENST00000418511.6	TSL:5	c.616C>T	p.Gln206*	stop_gained	Exon 8 of 8	ENSP00000453962.1	P0C7T8
	TMEM253	ENST00000878425.1		c.616C>T	p.Gln206*	stop_gained	Exon 8 of 8	ENSP00000548484.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399390 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690204

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078970

Other (OTH) AF: 0.00 AC: 0 AN: 58000

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Benign	0.88
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.014	N
PhyloP100		-0.45
Vest4		0.041
GERP RS		-1.2
PromoterAI		-0.014	Neutral
Mutation Taster		=174/26	polymorphism

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: rs1039472796; hg19: chr14-21571379;