rs387906719

Variant names:

• chrX-10523136-C-A
• rs387906719
• NM_000381.4:c.712G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000381.4(MID1):​c.712G>T​(p.Glu238*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 21)
• Consequence: MID1 NM_000381.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.15
• Publications: 4 publications found

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-10523136-C-A is Pathogenic according to our data. Variant chrX-10523136-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 29975.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MID1	NM_000381.4	MANE Select	c.712G>T	p.Glu238*	stop_gained	Exon 3 of 10	NP_000372.1
	MID1	NM_001098624.2		c.712G>T	p.Glu238*	stop_gained	Exon 3 of 10	NP_001092094.1
	MID1	NM_001193277.1		c.712G>T	p.Glu238*	stop_gained	Exon 3 of 10	NP_001180206.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MID1	ENST00000317552.9	TSL:1 MANE Select	c.712G>T	p.Glu238*	stop_gained	Exon 3 of 10	ENSP00000312678.4
	MID1	ENST00000380779.5	TSL:1	c.712G>T	p.Glu238*	stop_gained	Exon 3 of 10	ENSP00000370156.1
	MID1	ENST00000380780.5	TSL:1	c.712G>T	p.Glu238*	stop_gained	Exon 3 of 10	ENSP00000370157.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	X-linked Opitz G/BBB syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		7.2
Vest4		0.91
GERP RS		5.0
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs387906719; hg19: chrX-10491176;