rs200061253

Variant names:

• chrX-107854646-G-A
• rs200061253
• NM_012216.4:c.758G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_012216.4(MID2):​c.758G>A​(p.Arg253His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000419 in 1,096,961 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R253C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000042 (0 hom. 10 hem.)
• Consequence: MID2 NM_012216.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.81
• Publications: 0 publications found

Genes affected

MID2 (HGNC:7096): (midline 2) The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The protein localizes to microtubular structures in the cytoplasm. Alternate splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Feb 2009]

MID2 Gene-Disease associations (from GenCC):

• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual disability, X-linked 101

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27916482).
• BS2: High Hemizygotes in GnomAdExome4 at 10 Unknown,XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012216.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MID2	NM_012216.4	MANE Select	c.758G>A	p.Arg253His	missense	Exon 3 of 10	NP_036348.2	Q9UJV3-1
	MID2	NM_001382751.1		c.698G>A	p.Arg233His	missense	Exon 3 of 10	NP_001369680.1
	MID2	NM_052817.3		c.758G>A	p.Arg253His	missense	Exon 3 of 10	NP_438112.2	Q9UJV3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MID2	ENST00000262843.11	TSL:1 MANE Select	c.758G>A	p.Arg253His	missense	Exon 3 of 10	ENSP00000262843.6	Q9UJV3-1
	MID2	ENST00000443968.2	TSL:1	c.758G>A	p.Arg253His	missense	Exon 3 of 10	ENSP00000413976.2	Q9UJV3-2
	MID2	ENST00000921443.1		c.720+13261G>A		intron	N/A	ENSP00000591502.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000383 AC: 7 AN: 183006 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000489

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000419 AC: 46 AN: 1096961 Hom.: 0 Cov.: 28 AF XY: 0.0000276 AC XY: 10 AN XY: 362365

African (AFR) AF: 0.00 AC: 0 AN: 26370

American (AMR) AF: 0.00 AC: 0 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19368

East Asian (EAS) AF: 0.0000663 AC: 2 AN: 30176

South Asian (SAS) AF: 0.00 AC: 0 AN: 54074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.0000511 AC: 43 AN: 841150

Other (OTH) AF: 0.0000217 AC: 1 AN: 46054

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000332 Hom.: 1

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.2	L
PhyloP100		7.8
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.23
Sift	Benign	0.066	T
Sift4G	Benign	0.081	T
Polyphen		0.035	B
Vest4		0.35
MutPred		0.43		Loss of helix (P = 0.0376)
MVP		0.65
MPC		0.57
ClinPred		0.37	T
GERP RS		5.2
Varity_R		0.26
gMVP		0.73
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs200061253; hg19: chrX-107097876;