4-147633861-T-G

Variant names:

• chr4-147633861-T-G
• rs138365363
• NM_018241.3:c.976T>G

Variant summary

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

The NM_018241.3(TMEM184C):​c.976T>G​(p.Cys326Gly) 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. 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. C326R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TMEM184C NM_018241.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.77
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM184C	NM_018241.3	c.976T>G	p.Cys326Gly	missense_variant	Exon 9 of 10	ENST00000296582.8	NP_060711.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM184C	ENST00000296582.8	c.976T>G	p.Cys326Gly	missense_variant	Exon 9 of 10	2	NM_018241.3	ENSP00000296582.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	2.0	M
PhyloP100		7.8
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.65
Sift	Benign	0.13	T
Sift4G	Uncertain	0.042	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.63		Gain of disorder (P = 0.0016);
MVP		0.30
MPC		1.9
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.61
gMVP		0.82
Mutation Taster		=33/67	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs138365363; hg19: chr4-148555012;