NM_001190844.2:c.238G>T

Variant names:

• chr19-17448225-C-A
• rs780430984
• NM_001190844.2:c.238G>T

Variant summary

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

The NM_001190844.2(TMEM221):​c.238G>T​(p.Val80Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,211,900 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: TMEM221 NM_001190844.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.93
• Publications: 0 publications found

Genes affected

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

ENSG00000269035 (HGNC:):

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=0.17784396).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM221	NM_001190844.2	c.238G>T	p.Val80Leu	missense_variant	Exon 1 of 3	ENST00000341130.6	NP_001177773.1
TMEM221	XM_011527603.3	c.238G>T	p.Val80Leu	missense_variant	Exon 1 of 4		XP_011525905.1

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000248 AC: 3 AN: 1211900 Hom.: 0 Cov.: 28 AF XY: 0.00000168 AC XY: 1 AN XY: 593702

African (AFR) AF: 0.00 AC: 0 AN: 24416

American (AMR) AF: 0.00 AC: 0 AN: 14206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18972

East Asian (EAS) AF: 0.00 AC: 0 AN: 27276

South Asian (SAS) AF: 0.00 AC: 0 AN: 54798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4370

European-Non Finnish (NFE) AF: 0.00000303 AC: 3 AN: 990532

Other (OTH) AF: 0.00 AC: 0 AN: 48966

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.9
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.024
Sift	Benign	0.20	T
Sift4G	Benign	0.096	T
Vest4		0.22
MutPred		0.26		Loss of catalytic residue at V80 (P = 0.025);
MVP		0.040
ClinPred		0.14	T
GERP RS		2.0
PromoterAI		0.036	Neutral
Varity_R		0.15
gMVP		0.19
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs780430984; hg19: chr19-17559034;