1-203007539-T-C

Position:

• chr1-203007539-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138391.6(TMEM183A):​c.74T>C​(p.Leu25Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000215 in 1,395,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TMEM183A NM_138391.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.74

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

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=0.25342482).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMEM183A	NM_138391.6	c.74T>C	p.Leu25Pro	missense_variant	1/8	ENST00000367242.4	NP_612400.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMEM183A	ENST00000367242.4	c.74T>C	p.Leu25Pro	missense_variant	1/8	1	NM_138391.6	ENSP00000356211	P1
TMEM183A	ENST00000543891.5	n.137T>C		non_coding_transcript_exon_variant	1/4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1395522 Hom.: 0 Cov.: 31 AF XY: 0.00000290 AC XY: 2 AN XY: 689542

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: 0.00000277

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 14, 2023

The c.74T>C (p.L25P) alteration is located in exon 1 (coding exon 1) of the TMEM183A gene. This alteration results from a T to C substitution at nucleotide position 74, causing the leucine (L) at amino acid position 25 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	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.042
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.14
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.071	T
Polyphen		0.010	B
Vest4		0.62
MutPred		0.27		Gain of glycosylation at L25 (P = 0.0105);
MVP		0.093
MPC		0.98
ClinPred		0.91	D
GERP RS		5.3
Varity_R		0.63
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-202976667;