Genetic Variant TMEM184C:p.Phe223Cys (chr4-147631394-T-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_018241.3(TMEM184C):c.668T>G(p.Phe223Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,413,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

TMEM184C
NM_018241.3 missense, splice_region

Scores

Splicing: ADA: 0.003241

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.02

Publications

0 publications found

Variant links:

Genes affected

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

TMEM184C links:

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ACMG classification

Classification was made for transcript

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, 0.762

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM184C	NM_018241.3 link	c.668T>G	p.Phe223Cys	missense_variant, splice_region_variant	Exon 7 of 10	ENST00000296582.8	NP_060711.2	Q9NVA4-1
TMEM184C	XM_047415958.1 link	c.668T>G	p.Phe223Cys	missense_variant, splice_region_variant	Exon 7 of 8		XP_047271914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMEM184C	ENST00000296582.8 link	c.668T>G	p.Phe223Cys	missense_variant, splice_region_variant	Exon 7 of 10	2	NM_018241.3	ENSP00000296582.3	Q9NVA4-1
TMEM184C	ENST00000508208.5 link	c.668T>G	p.Phe223Cys	missense_variant, splice_region_variant	Exon 7 of 8	1		ENSP00000425940.1	A0A0C4DGC8
TMEM184C	ENST00000505999.5 link	n.83T>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 5	5		ENSP00000421159.1	H0Y8I5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000478

AC:

AN:

209158

AF XY:

0.00000873

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000495

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.08e-7

AC:

AN:

1413156

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

703042

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30104

American (AMR)

AF:

0.0000339

AC:

AN:

29524

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24266

East Asian (EAS)

AF:

0.00

AC:

AN:

38422

South Asian (SAS)

AF:

0.00

AC:

AN:

76794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53006

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5478

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1097306

Other (OTH)

AF:

0.00

AC:

AN:

58256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 27, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.668T>G (p.F223C) alteration is located in exon 7 (coding exon 7) of the TMEM184C gene. This alteration results from a T to G substitution at nucleotide position 668, causing the phenylalanine (F) at amino acid position 223 to be replaced by a cysteine (C). 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

Uncertain

0.55

BayesDel_addAF

Benign

0.0057

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.068

T;T

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.035

MetaRNN

Pathogenic

0.76

D;D

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.9

L;.

PhyloP100

8.0

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-2.4

N;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.019

D;D

Sift4G

Benign

0.18

T;T

Polyphen

1.0

D;.

Vest4

0.84

MutPred

0.74

Gain of catalytic residue at F223 (P = 0.1276);Gain of catalytic residue at F223 (P = 0.1276);

MVP

0.56

MPC

1.9

ClinPred

0.80

GERP RS

2.7

Varity_R

0.28

gMVP

0.88

Mutation Taster

=43/57

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0032

dbscSNV1_RF

Benign

0.14

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over