Genetic Variant SMIM24:p.Ala61Ser (chr19-3478477-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_001136503.2(SMIM24):c.181G>T(p.Ala61Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000633 in 1,547,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign 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: 𝑓 0.00039 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

SMIM24
NM_001136503.2 missense, splice_region

Scores

Splicing: ADA: 0.4513

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.749

Variant links:

Genes affected

SMIM24 (HGNC:37244): (small integral membrane protein 24) Predicted to be located in membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

SMIM24 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=0.01878646).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMIM24	NM_001136503.2 link	c.181G>T	p.Ala61Ser	missense_variant, splice_region_variant	Exon 3 of 4	ENST00000215531.6	NP_001129975.1	O75264

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SMIM24	ENST00000215531.6 link	c.181G>T	p.Ala61Ser	missense_variant, splice_region_variant	Exon 3 of 4	1	NM_001136503.2	ENSP00000215531.4	O75264
SMIM24	ENST00000587847.1 link	c.-30G>T		splice_region_variant	Exon 2 of 3	1		ENSP00000465692.1	K7EKM7
SMIM24	ENST00000587847.1 link	c.-30G>T		5_prime_UTR_variant	Exon 2 of 3	1		ENSP00000465692.1	K7EKM7
SMIM24	ENST00000591708.1 link	c.-30G>T		5_prime_UTR_variant	Exon 1 of 2	2		ENSP00000467484.1	K7EKM7

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

151940

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00136

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000910

AC:

AN:

153832

Hom.:

AF XY:

0.0000856

AC XY:

AN XY:

81784

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.0000422

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

0.0000279

AC:

AN:

1395670

Hom.:

Cov.:

AF XY:

0.0000334

AC XY:

AN XY:

688478

show subpopulations

Gnomad4 AFR exome

AF:

0.00115

Gnomad4 AMR exome

AF:

0.0000288

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.28e-7

Gnomad4 OTH exome

AF:

0.0000173

GnomAD4 genome

AF:

0.000388

AC:

AN:

151940

Hom.:

Cov.:

AF XY:

0.000458

AC XY:

AN XY:

74206

show subpopulations

Gnomad4 AFR

AF:

0.00136

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000515

Hom.:

Bravo

AF:

0.000586

ExAC

AF:

0.0000520

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.181G>T (p.A61S) alteration is located in exon 3 (coding exon 3) of the SMIM24 gene. This alteration results from a G to T substitution at nucleotide position 181, causing the alanine (A) at amino acid position 61 to be replaced by a serine (S). 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

0.096

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.010

Eigen

Benign

-0.022

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.46

M_CAP

Benign

0.012

MetaRNN

Benign

0.019

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.6

PROVEAN

Benign

-0.76

REVEL

Benign

0.089

Sift

Benign

0.77

Sift4G

Benign

0.66

Polyphen

0.99

Vest4

0.090

MVP

0.081

ClinPred

0.074

GERP RS

3.0

Varity_R

0.072

gMVP

0.012

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.45

dbscSNV1_RF

Benign

0.60

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