rs569981936

Variant names:

• chr14-21102097-C-T
• rs569981936
• NM_001395467.1:c.253C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001395465.1(TMEM253):​c.-105C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000172 in 1,551,078 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: 𝑓 0.000098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: TMEM253 NM_001395465.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.67
• 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.353876).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395465.1. 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.253C>T	p.Arg85Cys	missense	Exon 4 of 7	NP_001382396.1	P0C7T8
	TMEM253	NM_001395465.1		c.-105C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 7	NP_001382394.1
	TMEM253	NM_001395466.1		c.-105C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 6	NP_001382395.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM253	ENST00000556585.3	TSL:5 MANE Select	c.253C>T	p.Arg85Cys	missense	Exon 4 of 7	ENSP00000451229.2	P0C7T8
	TMEM253	ENST00000418511.6	TSL:5	c.253C>T	p.Arg85Cys	missense	Exon 5 of 8	ENSP00000453962.1	P0C7T8
	TMEM253	ENST00000878425.1		c.253C>T	p.Arg85Cys	missense	Exon 5 of 8	ENSP00000548484.1

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000913 AC: 14 AN: 153328 AF XY: 0.0000984

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: 0.000169

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000180 AC: 252 AN: 1398740 Hom.: 0 Cov.: 30 AF XY: 0.000181 AC XY: 125 AN XY: 689856

African (AFR) AF: 0.0000950 AC: 3 AN: 31590

American (AMR) AF: 0.00 AC: 0 AN: 35664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25116

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35736

South Asian (SAS) AF: 0.000265 AC: 21 AN: 79162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.000204 AC: 220 AN: 1078550

Other (OTH) AF: 0.000121 AC: 7 AN: 57968

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74490

African (AFR) AF: 0.0000241 AC: 1 AN: 41574

American (AMR) AF: 0.000131 AC: 2 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000151 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.000220 AC: 5

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	Benign	0.19
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.7
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.65
MVP		0.22
ClinPred		0.89	D
GERP RS		5.1
Varity_R		0.44
gMVP		0.44
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs569981936; hg19: chr14-21570256; COSMIC: COSV105919437; COSMIC: COSV105919437;