5-56937608-T-G

Position:

• chr5-56937608-T-G

Variant summary

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

The NM_001297599.2(MIER3):​c.406A>C​(p.Thr136Pro) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MIER3 NM_001297599.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.749

Genes affected

MIER3 (HGNC:26678): (MIER family member 3) Predicted to enable histone deacetylase binding activity and transcription corepressor activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Located in nucleoplasm. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

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=0.11871186).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MIER3	NM_001297599.2	c.406A>C	p.Thr136Pro	missense_variant	5/13	ENST00000381199.8	NP_001284528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MIER3	ENST00000381199.8	c.406A>C	p.Thr136Pro	missense_variant	5/13	1	NM_001297599.2	ENSP00000370596	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249156 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134648

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000548

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 Cov.: 30

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

May 26, 2024

The c.406A>C (p.T136P) alteration is located in exon 5 (coding exon 5) of the MIER3 gene. This alteration results from a A to C substitution at nucleotide position 406, causing the threonine (T) at amino acid position 136 to be replaced by a proline (P). 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	0.20
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	.;.;T;.;T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.031
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D;D;D;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	.;L;L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.2	N;N;N;N;N
REVEL	Benign	0.048
Sift	Benign	0.072	T;T;T;D;D
Sift4G	Benign	0.069	T;T;T;T;.
Polyphen		0.26	B;B;P;.;.
Vest4		0.26
MutPred		0.17		.;Loss of phosphorylation at T136 (P = 0.0304);Loss of phosphorylation at T136 (P = 0.0304);.;.;
MVP		0.082
MPC		0.88
ClinPred		0.30	T
GERP RS		3.7
Varity_R		0.14
gMVP		0.29

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

Other links and lift over

dbSNP: rs1219960080; hg19: chr5-56233435;