Variant 6-87337087-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001042493.3(SMIM8):c.56A>C(p.Glu19Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

SMIM8
NM_001042493.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.38

Variant links:

Genes affected

SMIM8 (HGNC:21401): (small integral membrane protein 8) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

SMIM8 links:

SMIM8 (HGNC:):

SMIM8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.028856635).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMIM8	NM_001042493.3 linkuse as main transcript	c.56A>C	p.Glu19Ala	missense_variant	3/4	ENST00000392863.6	NP_001035958.1	Q96KF7
SMIM8	NM_020425.6 linkuse as main transcript	c.56A>C	p.Glu19Ala	missense_variant	2/3		NP_065158.3	Q96KF7
SMIM8	NM_001287445.2 linkuse as main transcript	c.56A>C	p.Glu19Ala	missense_variant	2/3		NP_001274374.1	V9GYF9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMIM8	ENST00000392863.6 linkuse as main transcript	c.56A>C	p.Glu19Ala	missense_variant	3/4	1	NM_001042493.3	ENSP00000376603.1		Q96KF7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251282

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad SAS 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:

0.00000342

AC:

AN:

1460916

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726742

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 16, 2024

The c.56A>C (p.E19A) alteration is located in exon 3 (coding exon 1) of the SMIM8 gene. This alteration results from a A to C substitution at nucleotide position 56, causing the glutamic acid (E) at amino acid position 19 to be replaced by an alanine (A). 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

0.062

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.0037

T;T;T;T;T

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.24

.;T;.;T;.

M_CAP

Benign

0.0012

MetaRNN

Benign

0.029

T;T;T;T;T

MetaSVM

Benign

-0.99

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.090

.;N;N;.;.

REVEL

Benign

0.13

Sift

Benign

0.71

.;T;T;.;.

Sift4G

Benign

0.37

T;T;T;T;T

Polyphen

0.0

B;B;B;.;B

Vest4

0.10

MutPred

0.17

Loss of ubiquitination at K18 (P = 0.0193);Loss of ubiquitination at K18 (P = 0.0193);Loss of ubiquitination at K18 (P = 0.0193);Loss of ubiquitination at K18 (P = 0.0193);Loss of ubiquitination at K18 (P = 0.0193);

MVP

0.014

MPC

0.031

ClinPred

0.17

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.054

gMVP

0.54

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