4-147624933-G-C

Variant names:

• chr4-147624933-G-C
• rs377518448
• NM_018241.3:c.421G>C

Variant summary

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

The NM_018241.3(TMEM184C):​c.421G>C​(p.Val141Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. V141I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMEM184C NM_018241.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.78
• Publications: 0 publications found

Genes affected

TMEM184C (HGNC:25587): (transmembrane protein 184C) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.24708873).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM184C	NM_018241.3	c.421G>C	p.Val141Leu	missense_variant	Exon 4 of 10	ENST00000296582.8	NP_060711.2
TMEM184C	XM_047415958.1	c.421G>C	p.Val141Leu	missense_variant	Exon 4 of 8		XP_047271914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM184C	ENST00000296582.8	c.421G>C	p.Val141Leu	missense_variant	Exon 4 of 10	2	NM_018241.3	ENSP00000296582.3
TMEM184C	ENST00000508208.5	c.421G>C	p.Val141Leu	missense_variant	Exon 4 of 8	1		ENSP00000425940.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461614 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727118

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111874

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.039	T;T
Eigen	Benign	-0.066
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;.
PhyloP100		6.8
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.079
Sift	Benign	0.36	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.13	B;.
Vest4		0.35
MutPred		0.61		Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);
MVP		0.30
MPC		0.71
ClinPred		0.74	D
GERP RS		4.3
Varity_R		0.090
gMVP		0.68
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs377518448; hg19: chr4-148546084;