14-21102421-T-C

Variant names:

• chr14-21102421-T-C
• rs759131097
• NM_001395467.1:c.293T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001395467.1(TMEM253):​c.293T>C​(p.Ile98Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,399,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TMEM253 NM_001395467.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.593
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.098516375).

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.293T>C	p.Ile98Thr	missense	Exon 5 of 7	NP_001382396.1	P0C7T8
	TMEM253	NM_001146683.2		c.293T>C	p.Ile98Thr	missense	Exon 6 of 8	NP_001140155.1	P0C7T8
	TMEM253	NM_001395464.1		c.182T>C	p.Ile61Thr	missense	Exon 5 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.293T>C	p.Ile98Thr	missense	Exon 5 of 7	ENSP00000451229.2	P0C7T8
	TMEM253	ENST00000418511.6	TSL:5	c.293T>C	p.Ile98Thr	missense	Exon 6 of 8	ENSP00000453962.1	P0C7T8
	TMEM253	ENST00000878425.1		c.293T>C	p.Ile98Thr	missense	Exon 6 of 8	ENSP00000548484.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000130 AC: 2 AN: 154074 AF XY: 0.0000122

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000214 AC: 3 AN: 1399390 Hom.: 0 Cov.: 31 AF XY: 0.00000290 AC XY: 2 AN XY: 690200

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: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79234

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078966

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

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000410 AC: 1

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	Uncertain	0.39
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.099	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.59
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.10
Sift	Benign	0.088	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.012	B
Vest4		0.28
MutPred		0.36		Gain of catalytic residue at V93 (P = 0.0032)
MVP		0.030
ClinPred		0.093	T
GERP RS		3.1
Varity_R		0.11
gMVP		0.15
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs759131097; hg19: chr14-21570580;