chr4-25928336-G-T

Position:

• chr4-25928336-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001145432.3(SMIM20):​c.133G>T​(p.Ala45Ser) 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. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMIM20 NM_001145432.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.04

Genes affected

SMIM20 (HGNC:37260): (small integral membrane protein 20) Involved in mitochondrial cytochrome c oxidase assembly. Located in mitochondrial inner membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27370256).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMIM20	NM_001145432.3	c.133G>T	p.Ala45Ser	missense_variant	2/3	ENST00000506197.3
SMIM20	NM_001394130.1	c.110-818G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMIM20	ENST00000506197.3	c.133G>T	p.Ala45Ser	missense_variant	2/3	1	NM_001145432.3	P1
SMIM20	ENST00000514384.1	c.110-818G>T		intron_variant		5
SMIM20	ENST00000515764.2	n.348G>T		non_coding_transcript_exon_variant	2/3	5
SMIM20	ENST00000522137.1	n.122G>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

Sep 30, 2021

The c.133G>T (p.A45S) alteration is located in exon 2 (coding exon 2) of the SMIM20 gene. This alteration results from a G to T substitution at nucleotide position 133, causing the alanine (A) at amino acid position 45 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	0.085
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.48	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
Sift4G	Uncertain	0.049	D;T
Vest4		0.27
MutPred		0.34		Gain of relative solvent accessibility (P = 0.005);.;
MVP		0.17
ClinPred		0.86	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.082
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr4-25929958;