Variant 19-17448305-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001190844.2(TMEM221):c.158T>C(p.Leu53Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,220,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

TMEM221
NM_001190844.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.164

Variant links:

Genes affected

TMEM221 (HGNC:21943): (transmembrane protein 221) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM221 links:

ENSG00000269035 (HGNC:):

ENSG00000269035 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17533818).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM221	NM_001190844.2 linkuse as main transcript	c.158T>C	p.Leu53Pro	missense_variant	1/3	ENST00000341130.6	NP_001177773.1	A6NGB7
TMEM221	XM_011527603.3 linkuse as main transcript	c.158T>C	p.Leu53Pro	missense_variant	1/4		XP_011525905.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TMEM221	ENST00000341130.6 linkuse as main transcript	c.158T>C	p.Leu53Pro	missense_variant	1/3	2	NM_001190844.2	ENSP00000342162.5	A6NGB7
ENSG00000269035	ENST00000594663.1 linkuse as main transcript	c.276-3021T>C		intron_variant		3		ENSP00000472415.1	M0R296
TMEM221	ENST00000593461.1 linkuse as main transcript	n.5T>C		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

150624

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000663

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1069726

Hom.:

Cov.:

AF XY:

0.0000118

AC XY:

AN XY:

509776

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000766

Gnomad4 OTH exome

AF:

0.0000478

GnomAD4 genome

AF:

0.0000133

AC:

AN:

150624

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73502

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000663

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

The c.158T>C (p.L53P) alteration is located in exon 1 (coding exon 1) of the TMEM221 gene. This alteration results from a T to C substitution at nucleotide position 158, causing the leucine (L) at amino acid position 53 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Uncertain

0.015

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.021

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.36

M_CAP

Benign

0.056

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.6

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

0.40

REVEL

Uncertain

0.51

Sift

Uncertain

0.0090

Sift4G

Benign

0.087

Vest4

0.19

MutPred

0.28

Gain of loop (P = 0.0097);

MVP

0.42

ClinPred

0.79

GERP RS

2.9

Varity_R

0.12

gMVP

0.19

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over