1-203016097-C-T

Variant names:

• chr1-203016097-C-T
• NM_138391.6:c.665C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_138391.6(TMEM183A):​c.665C>T​(p.Pro222Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMEM183A NM_138391.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• Publications: 0 publications found

Genes affected

TMEM183A (HGNC:20173): (transmembrane protein 183A) Predicted to be involved in regulation of protein stability. Predicted to be integral component of membrane. Predicted to be part of SCF ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138391.6. 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
	TMEM183A	NM_138391.6	MANE Select	c.665C>T	p.Pro222Leu	missense	Exon 5 of 8	NP_612400.3
	TMEM183A	NM_001322956.2		c.662C>T	p.Pro221Leu	missense	Exon 5 of 8	NP_001309885.1
	TMEM183A	NM_001322958.2		c.575C>T	p.Pro192Leu	missense	Exon 4 of 7	NP_001309887.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM183A	ENST00000367242.4	TSL:1 MANE Select	c.665C>T	p.Pro222Leu	missense	Exon 5 of 8	ENSP00000356211.3	Q8IXX5-1
	TMEM183A	ENST00000881146.1		c.665C>T	p.Pro222Leu	missense	Exon 5 of 9	ENSP00000551205.1
	TMEM183A	ENST00000965091.1		c.698C>T	p.Pro233Leu	missense	Exon 5 of 8	ENSP00000635150.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1461882 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

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	0.24
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.025	T
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.28
Sift	Benign	0.14	T
Sift4G	Uncertain	0.0070	D
Polyphen		0.99	D
Vest4		0.89
MutPred		0.34		Loss of disorder (P = 0.0244)
MVP		0.24
MPC		1.5
ClinPred		0.93	D
GERP RS		5.4
Varity_R		0.14
gMVP		0.63
Mutation Taster		=42/58	disease causing

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

hg19: chr1-202985225;