chr4-147628428-G-A

Variant names:

• chr4-147628428-G-A
• rs1056354158
• NM_018241.3:c.565G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018241.3(TMEM184C):​c.565G>A​(p.Val189Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000521 in 1,613,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: TMEM184C NM_018241.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.19
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.033072382).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM184C	NM_018241.3	c.565G>A	p.Val189Ile	missense_variant	Exon 5 of 10	ENST00000296582.8	NP_060711.2
TMEM184C	XM_047415958.1	c.565G>A	p.Val189Ile	missense_variant	Exon 5 of 8		XP_047271914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM184C	ENST00000296582.8	c.565G>A	p.Val189Ile	missense_variant	Exon 5 of 10	2	NM_018241.3	ENSP00000296582.3
TMEM184C	ENST00000508208.5	c.565G>A	p.Val189Ile	missense_variant	Exon 5 of 8	1		ENSP00000425940.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152020 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 250814 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000547 AC: 80 AN: 1461206 Hom.: 0 Cov.: 30 AF XY: 0.0000523 AC XY: 38 AN XY: 726886

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39660

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000675 AC: 75 AN: 1111758

Other (OTH) AF: 0.0000497 AC: 3 AN: 60360

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152020 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74236

African (AFR) AF: 0.0000242 AC: 1 AN: 41378

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 28, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.565G>A (p.V189I) alteration is located in exon 5 (coding exon 5) of the TMEM184C gene. This alteration results from a G to A substitution at nucleotide position 565, causing the valine (V) at amino acid position 189 to be replaced by an isoleucine (I). 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	Benign	0.064
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	10
DANN	Benign	0.39
DEOGEN2	Benign	0.025	T;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.83	T;D
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.033	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.81	N;.
PhyloP100		2.2
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.62	N;N
REVEL	Benign	0.10
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.10
MutPred		0.47		Loss of catalytic residue at V189 (P = 0.0188);Loss of catalytic residue at V189 (P = 0.0188);
MVP		0.11
MPC		0.55
ClinPred		0.022	T
GERP RS		-0.90
Varity_R		0.012
gMVP		0.076
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1056354158; hg19: chr4-148549579; COSMIC: COSV56855237; COSMIC: COSV56855237;