8-30645518-T-C

Position:

• chr8-30645518-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001206847.2(SMIM18):​c.209T>C​(p.Val70Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMIM18 NM_001206847.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.46

Genes affected

SMIM18 (HGNC:42973): (small integral membrane protein 18) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

GTF2E2 (HGNC:4651): (general transcription factor IIE subunit 2) The general transcription factor IIE (TFIIE) is part of the RNA polymerase II transcription initiation complex, recruiting TFIIH and being essential for promoter clearance by RNA polymerase II. TFIIE is a heterodimer (and sometimes heterotetramer) of alpha and beta subunits. The protein encoded by this gene represents the beta subunit of TFIIE. [provided by RefSeq, Jan 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20951498).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMIM18	NM_001206847.2	c.209T>C	p.Val70Ala	missense_variant	3/3	ENST00000517349.2	NP_001193776.1
GTF2E2	NM_002095.6	c.166+7915A>G		intron_variant		ENST00000355904.9	NP_002086.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMIM18	ENST00000517349.2	c.209T>C	p.Val70Ala	missense_variant	3/3	2	NM_001206847.2	ENSP00000428858	P1
GTF2E2	ENST00000355904.9	c.166+7915A>G		intron_variant		1	NM_002095.6	ENSP00000348168	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2023

The c.209T>C (p.V70A) alteration is located in exon 3 (coding exon 1) of the SMIM18 gene. This alteration results from a T to C substitution at nucleotide position 209, causing the valine (V) at amino acid position 70 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	0.15
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.083
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.32
MutPred		0.23		Loss of sheet (P = 0.0104);
MVP		0.10
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.31
gMVP		0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-30503035;