rs1556004400

Positions:

• chrX-10459732-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_000381.4(MID1):​c.1361A>G​(p.Gln454Arg) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: MID1 NM_000381.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U: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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-10459732-T-C is Pathogenic according to our data. Variant chrX-10459732-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 522030.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MID1	NM_000381.4	c.1361A>G	p.Gln454Arg	missense_variant	8/10	ENST00000317552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MID1	ENST00000317552.9	c.1361A>G	p.Gln454Arg	missense_variant	8/10	1	NM_000381.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

X-linked Opitz G/BBB syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T;T;T;T;T;.;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.82	T;.;.;.;.;.;T;D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.6	L;L;L;L;L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.012	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D;D;D;D;.
Polyphen		0.96	D;D;D;D;D;D;.;.
Vest4		0.88
MutPred		0.41		Gain of MoRF binding (P = 0.011);Gain of MoRF binding (P = 0.011);Gain of MoRF binding (P = 0.011);Gain of MoRF binding (P = 0.011);Gain of MoRF binding (P = 0.011);Gain of MoRF binding (P = 0.011);Gain of MoRF binding (P = 0.011);Gain of MoRF binding (P = 0.011);
MVP		0.95
MPC		2.0
ClinPred		0.94	D
GERP RS		5.3
Varity_R		0.63
gMVP		0.72

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

LitVar

Other links and lift over

dbSNP: rs1556004400; hg19: chrX-10427772;