14-39247296-C-T

Position:

• chr14-39247296-C-T

Variant summary

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

The ENST00000640607.2(MIA2):​c.722C>T​(p.Ser241Leu) 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: MIA2 ENST00000640607.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.346

Genes affected

MIA2 (HGNC:18432): (MIA SH3 domain ER export factor 2) This gene encodes s receptor in the endoplasmic reticulum, which plays a role in the export of large pre-chylomicrons and pre-very low density lipoproteins (pre-VLDLs). Three major classes of transcripts are generated from this gene- melanoma inhibitory activity 2-specific transcripts, cTAGE family member 5-specific transcripts and transcripts that include exons from both these transcript species (TANGO1-like or TALI). Additionally, alternative splicing in these transcripts results in multiple transcript variants encoding multiple isoforms. [provided by RefSeq, Sep 2016]

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=0.08260533).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MIA2	NM_001329214.4	c.722C>T	p.Ser241Leu	missense_variant	4/29	ENST00000640607.2	NP_001316143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MIA2	ENST00000640607.2	c.722C>T	p.Ser241Leu	missense_variant	4/29	1	NM_001329214.4	ENSP00000491014	P2
MIA2	ENST00000280082.4	c.722C>T	p.Ser241Leu	missense_variant	4/6	1		ENSP00000280082
MIA2	ENST00000553728.1	c.722C>T	p.Ser241Leu	missense_variant	4/28	5		ENSP00000452252	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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 22, 2023

The c.722C>T (p.S241L) alteration is located in exon 4 (coding exon 4) of the MIA2 gene. This alteration results from a C to T substitution at nucleotide position 722, causing the serine (S) at amino acid position 241 to be replaced by a leucine (L). 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	0.088
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.044	.;.;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.79	T;D;D
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.083	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	.;M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N;N;.
REVEL	Benign	0.050
Sift	Benign	0.24	T;T;.
Sift4G	Benign	0.27	T;T;.
Polyphen		0.091, 0.055	.;B;B
Vest4		0.099
MutPred		0.32		Gain of catalytic residue at P245 (P = 0.0061);Gain of catalytic residue at P245 (P = 0.0061);Gain of catalytic residue at P245 (P = 0.0061);
MVP		0.46
MPC		0.038
ClinPred		0.65	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.074

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: chr14-39716500; COSMIC: COSV54483626;