X-10449448-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_000381.4(MID1):c.1924A>C(p.Thr642Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. T642T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MID1 NM_000381.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.51

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-10449448-T-G is Pathogenic according to our data. Variant chrX-10449448-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1299558.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MID1	NM_000381.4	c.1924A>C	p.Thr642Pro	missense_variant	10/10	ENST00000317552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MID1	ENST00000317552.9	c.1924A>C	p.Thr642Pro	missense_variant	10/10	1	NM_000381.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked Opitz G/BBB syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Aug 10, 2021

PM2, PP1, PP2, PP3, PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;D;D;D;D;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;.;.;.;.;.
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.1	M;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.012	D;D;D;D;D;D
Sift4G	Uncertain	0.025	D;D;D;D;D;D
Polyphen		0.96	D;D;D;D;D;D
Vest4		0.50
MutPred		0.76		Loss of glycosylation at T642 (P = 0.0433);Loss of glycosylation at T642 (P = 0.0433);Loss of glycosylation at T642 (P = 0.0433);Loss of glycosylation at T642 (P = 0.0433);Loss of glycosylation at T642 (P = 0.0433);Loss of glycosylation at T642 (P = 0.0433);
MVP		0.93
MPC		1.9
ClinPred		0.92	D
GERP RS		5.5
Varity_R		0.95
gMVP		0.83

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: chrX-10417488;