Genetic Variant TMEM221:p.Val80Met (chr19-17448225-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001190844.2(TMEM221):c.238G>A(p.Val80Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000825 in 1,211,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V80L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.3e-7 ( 0 hom. )

Consequence

TMEM221
NM_001190844.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.93

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

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=0.17865461).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM221	NM_001190844.2 link	c.238G>A	p.Val80Met	missense_variant	Exon 1 of 3	ENST00000341130.6	NP_001177773.1	A6NGB7
TMEM221	XM_011527603.3 link	c.238G>A	p.Val80Met	missense_variant	Exon 1 of 4		XP_011525905.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMEM221	ENST00000341130.6 link	c.238G>A	p.Val80Met	missense_variant	Exon 1 of 3	2	NM_001190844.2	ENSP00000342162.5	A6NGB7
ENSG00000269035	ENST00000594663.1 link	c.276-2941G>A		intron_variant	Intron 2 of 3	3		ENSP00000472415.1	M0R296
TMEM221	ENST00000593461.1 link	n.85G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2
ENSG00000295860	ENST00000733255.1 link	n.119+14C>T		intron_variant	Intron 1 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000307

AC:

AN:

32522

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000318

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:

8.25e-7

AC:

AN:

1211902

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

593704

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24416

American (AMR)

AF:

0.00

AC:

AN:

14208

Ashkenazi Jewish (ASJ)

AF:

0.0000527

AC:

AN:

18972

East Asian (EAS)

AF:

0.00

AC:

AN:

27276

South Asian (SAS)

AF:

0.00

AC:

AN:

54798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4370

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

990532

Other (OTH)

AF:

0.00

AC:

AN:

48966

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.089

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.035

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.68

M_CAP

Benign

0.0096

MetaRNN

Benign

0.18

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PhyloP100

1.9

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.62

REVEL

Benign

0.048

Sift

Uncertain

0.027

Sift4G

Uncertain

0.034

Vest4

0.37

MutPred

0.32

Loss of catalytic residue at V80 (P = 0.1228);

MVP

0.040

ClinPred

0.28

GERP RS

2.0

PromoterAI

0.037

Neutral

(source)

Varity_R

0.099

gMVP

0.18

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over