Genetic Variant TMEM221:p.Val80Leu (chr19-17448225-C-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001190844.2(TMEM221):c.238G>C(p.Val80Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,363,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000097 ( 0 hom. )

Consequence

TMEM221
NM_001190844.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.034656852).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM221	NM_001190844.2 link	c.238G>C	p.Val80Leu	missense_variant	Exon 1 of 3	ENST00000341130.6	NP_001177773.1	A6NGB7
TMEM221	XM_011527603.3 link	c.238G>C	p.Val80Leu	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>C	p.Val80Leu	missense_variant	Exon 1 of 3	2	NM_001190844.2	ENSP00000342162.5	A6NGB7
ENSG00000269035	ENST00000594663.1 link	c.276-2941G>C		intron_variant	Intron 2 of 3	3		ENSP00000472415.1	M0R296
TMEM221	ENST00000593461.1 link	n.85G>C		non_coding_transcript_exon_variant	Exon 1 of 2	2
ENSG00000295860	ENST00000733255.1 link	n.119+14C>G		intron_variant	Intron 1 of 4

Frequencies

GnomAD3 genomes

AF:

0.000336

AC:

AN:

151702

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000246

AC:

AN:

32522

AF XY:

0.000247

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000247

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:

0.0000965

AC:

117

AN:

1211902

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

593704

show subpopulations

African (AFR)

AF:

0.00160

AC:

AN:

24416

American (AMR)

AF:

0.000141

AC:

AN:

14208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18972

East Asian (EAS)

AF:

0.00

AC:

AN:

27276

South Asian (SAS)

AF:

0.000912

AC:

AN:

54798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28364

Middle Eastern (MID)

AF:

0.000229

AC:

AN:

4370

European-Non Finnish (NFE)

AF:

0.0000111

AC:

AN:

990532

Other (OTH)

AF:

0.000286

AC:

AN:

48966

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000356

AC:

AN:

151810

Hom.:

Cov.:

AF XY:

0.000377

AC XY:

AN XY:

74204

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41508

American (AMR)

AF:

0.0000655

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000414

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67888

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000325

ExAC

AF:

0.000474

AC:

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 14, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.238G>C (p.V80L) alteration is located in exon 1 (coding exon 1) of the TMEM221 gene. This alteration results from a G to C substitution at nucleotide position 238, causing the valine (V) at amino acid position 80 to be replaced by a leucine (L). 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

0.20

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.041

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.53

M_CAP

Benign

0.0063

MetaRNN

Benign

0.035

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

PhyloP100

1.9

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.92

REVEL

Benign

0.021

Sift

Benign

0.20

Sift4G

Benign

0.096

Vest4

0.22

MutPred

0.26

Loss of catalytic residue at V80 (P = 0.025);

MVP

0.040

ClinPred

0.039

GERP RS

2.0

PromoterAI

0.052

Neutral

(source)

Varity_R

0.15

gMVP

0.19

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over