chrX-10449709-T-C

Position:

chrX-10449709-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP5BS2

The NM_000381.4(MID1):c.1663A>G(p.Ile555Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,199,830 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000092 ( 0 hom. 2 hem. )

Consequence

MID1
NM_000381.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 3.33

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP5

Variant X-10449709-T-C is Pathogenic according to our data. Variant chrX-10449709-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547526.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MID1	NM_000381.4 linkuse as main transcript	c.1663A>G	p.Ile555Val	missense_variant	10/10	ENST00000317552.9	NP_000372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MID1	ENST00000317552.9 linkuse as main transcript	c.1663A>G	p.Ile555Val	missense_variant	10/10	1	NM_000381.4	ENSP00000312678	P1	O15344-1

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

112000

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34164

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000563

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000558

AC:

AN:

179208

Hom.:

AF XY:

0.00

AC XY:

AN XY:

65020

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000127

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000919

AC:

AN:

1087830

Hom.:

Cov.:

AF XY:

0.00000566

AC XY:

AN XY:

353490

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000186

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000268

AC:

AN:

112000

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34164

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000563

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

X-linked Opitz G/BBB syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 01, 2016

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 19, 2023

Variant summary: MID1 c.1663A>G (p.Ile555Val) results in a conservative amino acid change located in the SPRY domain (IPR001870) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.7e-05 in 111076 control chromosomes (i.e., 2 heterozygous females and 1 hemizygous male; gnomAD v3.1.2). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1663A>G has been reported in the literature in at least one hemizygote affected with Opitz G/BBB syndrome (e.g., Ferrentino_2007). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 17221865). One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.0019

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Benign

0.56

DEOGEN2

Benign

0.14

T;T;T;T;T;T

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.86

D;.;.;.;.;.

M_CAP

Benign

0.054

MetaRNN

Uncertain

0.60

D;D;D;D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.25

N;N;N;N;N;N

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Benign

0.48

PROVEAN

Benign

0.29

N;N;N;N;N;N

REVEL

Benign

0.25

Sift

Benign

0.78

T;T;T;T;T;T

Sift4G

Benign

0.83

T;T;T;T;T;T

Polyphen

0.0020

B;B;B;B;B;B

Vest4

0.67

MutPred

0.78

Loss of ubiquitination at K560 (P = 0.1139);Loss of ubiquitination at K560 (P = 0.1139);Loss of ubiquitination at K560 (P = 0.1139);Loss of ubiquitination at K560 (P = 0.1139);Loss of ubiquitination at K560 (P = 0.1139);Loss of ubiquitination at K560 (P = 0.1139);

MVP

0.94

MPC

0.70

ClinPred

0.11

GERP RS

5.5

Varity_R

0.17

gMVP

0.17

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over