Genetic Variant TMEM184C:p.Met164Thr (chr4-147625003-T-C) – 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.491T>C(p.Met164Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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

TMEM184C
NM_018241.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.01

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, 0.799

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM184C	NM_018241.3 link	c.491T>C	p.Met164Thr	missense_variant	Exon 4 of 10	ENST00000296582.8	NP_060711.2	Q9NVA4-1
TMEM184C	XM_047415958.1 link	c.491T>C	p.Met164Thr	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 link	c.491T>C	p.Met164Thr	missense_variant	Exon 4 of 10	2	NM_018241.3	ENSP00000296582.3		Q9NVA4-1
TMEM184C	ENST00000508208.5 link	c.491T>C	p.Met164Thr	missense_variant	Exon 4 of 8	1		ENSP00000425940.1		A0A0C4DGC8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461422

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727032

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39618

South Asian (SAS)

AF:

0.00

AC:

AN:

86224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111778

Other (OTH)

AF:

0.0000166

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 27, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.491T>C (p.M164T) alteration is located in exon 4 (coding exon 4) of the TMEM184C gene. This alteration results from a T to C substitution at nucleotide position 491, causing the methionine (M) at amino acid position 164 to be replaced by a threonine (T). 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

0.51

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;T

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.031

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.7

L;.

PhyloP100

8.0

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.6

D;D

REVEL

Uncertain

0.47

Sift

Uncertain

0.021

D;D

Sift4G

Uncertain

0.036

D;D

Polyphen

1.0

D;.

Vest4

0.88

MutPred

0.65

Gain of catalytic residue at M164 (P = 0.0543);Gain of catalytic residue at M164 (P = 0.0543);

MVP

0.69

MPC

0.96

ClinPred

0.98

GERP RS

5.2

Varity_R

0.53

gMVP

0.83

Mutation Taster

=6/94

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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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4-147625003-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over