Genetic Variant MID1:p.Arg495Gly (chrX-10455042-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_000381.4(MID1):c.1483C>G(p.Arg495Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R495Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 22)

Consequence

MID1
NM_000381.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.67

Publications

6 publications found

Variant links:

Genes affected

MID1 (HGNC:7095): (midline 1) The protein encoded by this gene is a member of the tripartite motif (TRIM) family, also known as the 'RING-B box-coiled coil' (RBCC) subgroup of RING finger proteins. 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. This protein forms homodimers which associate with microtubules in the cytoplasm. The protein is likely involved in the formation of multiprotein structures acting as anchor points to microtubules. Mutations in this gene have been associated with the X-linked form of Opitz syndrome, which is characterized by midline abnormalities such as cleft lip, laryngeal cleft, heart defects, hypospadias, and agenesis of the corpus callosum. This gene was also the first example of a gene subject to X inactivation in human while escaping it in mouse. Alternative promoter use, alternative splicing and alternative polyadenylation result in multiple transcript variants that have different tissue specificities. [provided by RefSeq, Dec 2016]

MID1 Gene-Disease associations (from GenCC):

X-linked Opitz G/BBB syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

MID1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.806

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000381.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MID1	NM_000381.4	MANE Select	c.1483C>G	p.Arg495Gly	missense	Exon 9 of 10	NP_000372.1
MID1	NM_001098624.2		c.1483C>G	p.Arg495Gly	missense	Exon 9 of 10	NP_001092094.1
MID1	NM_001193277.1		c.1483C>G	p.Arg495Gly	missense	Exon 9 of 10	NP_001180206.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MID1	ENST00000317552.9	TSL:1 MANE Select	c.1483C>G	p.Arg495Gly	missense	Exon 9 of 10	ENSP00000312678.4
MID1	ENST00000380779.5	TSL:1	c.1483C>G	p.Arg495Gly	missense	Exon 9 of 10	ENSP00000370156.1
MID1	ENST00000380780.5	TSL:1	c.1483C>G	p.Arg495Gly	missense	Exon 9 of 10	ENSP00000370157.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Uncertain

0.096

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.81

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PhyloP100

3.7

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.5

REVEL

Benign

0.17

Sift

Benign

0.18

Sift4G

Uncertain

0.018

Polyphen

0.90

Vest4

0.85

MutPred

0.27

Loss of MoRF binding (P = 0.0061)

MVP

0.83

MPC

1.7

ClinPred

0.92

GERP RS

4.9

Varity_R

0.20

gMVP

0.83

Mutation Taster

=23/77

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over