Genetic Variant TMEM184A:p.Ser393Phe (chr7-1547016-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001097620.2(TMEM184A):c.1178C>T(p.Ser393Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000747 in 1,471,574 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000073 ( 2 hom. )

Consequence

TMEM184A
NM_001097620.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.19

Variant links:

Genes affected

TMEM184A (HGNC:28797): (transmembrane protein 184A) Predicted to enable heparin binding activity. Predicted to act upstream of or within germ-line sex determination; regulation of protein localization; and regulation of secretion. Predicted to be located in cytoplasmic vesicle; perinuclear region of cytoplasm; and plasma membrane. Predicted to be active in early endosome membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM184A links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08728114).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM184A	NM_001097620.2 link	c.1178C>T	p.Ser393Phe	missense_variant	Exon 9 of 9	ENST00000297477.10	NP_001091089.1	Q6ZMB5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TMEM184A	ENST00000297477.10 link	c.1178C>T	p.Ser393Phe	missense_variant	Exon 9 of 9	1	NM_001097620.2	ENSP00000297477.4	Q6ZMB5
TMEM184A	ENST00000319018.12 link	n.*601C>T		non_coding_transcript_exon_variant	Exon 8 of 8	5		ENSP00000326348.7	F8W8F1
TMEM184A	ENST00000468535.5 link	n.2056C>T		non_coding_transcript_exon_variant	Exon 6 of 6	2
TMEM184A	ENST00000319018.12 link	n.*601C>T		3_prime_UTR_variant	Exon 8 of 8	5		ENSP00000326348.7	F8W8F1

Frequencies

GnomAD3 genomes

AF:

0.0000101

AC:

AN:

99160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000326

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000729

AC:

AN:

1372304

Hom.:

Cov.:

AF XY:

0.0000118

AC XY:

AN XY:

680810

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000101

AC:

AN:

99270

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

48238

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000326

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000876

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1178C>T (p.S393F) alteration is located in exon 9 (coding exon 8) of the TMEM184A gene. This alteration results from a C to T substitution at nucleotide position 1178, causing the serine (S) at amino acid position 393 to be replaced by a phenylalanine (F). 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

0.086

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.022

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.40

M_CAP

Benign

0.0084

MetaRNN

Benign

0.087

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.4

REVEL

Benign

0.076

Sift

Uncertain

0.024

Sift4G

Uncertain

0.018

Polyphen

0.0

Vest4

0.15

MutPred

0.27

Loss of glycosylation at S393 (P = 0.0044);

MVP

0.17

MPC

0.11

ClinPred

0.32

GERP RS

3.1

Varity_R

0.11

gMVP

0.45

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over