X-10501436-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001193278.1(MID1):​c.880G>A​(p.Glu294Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,153,689 control chromosomes in the GnomAD database, including 80 homozygotes. There are 4,381 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 8/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0076 ( 4 hom., 223 hem., cov: 23)
Exomes 𝑓: 0.013 ( 76 hom. 4158 hem. )

Consequence

MID1
NM_001193278.1 missense

Scores

9

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.61
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0039096773).
BP6
Variant X-10501436-C-T is Benign according to our data. Variant chrX-10501436-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-10501436-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00757 (845/111660) while in subpopulation NFE AF= 0.0135 (715/53136). AF 95% confidence interval is 0.0126. There are 4 homozygotes in gnomad4. There are 223 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MID1NM_000381.4 linkuse as main transcriptc.757-5745G>A intron_variant ENST00000317552.9 NP_000372.1 O15344-1A0A024RBV4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MID1ENST00000317552.9 linkuse as main transcriptc.757-5745G>A intron_variant 1 NM_000381.4 ENSP00000312678.4 O15344-1
MID1ENST00000380782.6 linkuse as main transcriptc.757-5745G>A intron_variant 1 ENSP00000370159.1 O15344-2

Frequencies

GnomAD3 genomes
AF:
0.00758
AC:
846
AN:
111607
Hom.:
4
Cov.:
23
AF XY:
0.00663
AC XY:
224
AN XY:
33767
show subpopulations
Gnomad AFR
AF:
0.00260
Gnomad AMI
AF:
0.0118
Gnomad AMR
AF:
0.00143
Gnomad ASJ
AF:
0.00228
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000377
Gnomad FIN
AF:
0.00284
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0135
Gnomad OTH
AF:
0.00268
GnomAD3 exomes
AF:
0.00659
AC:
645
AN:
97874
Hom.:
4
AF XY:
0.00670
AC XY:
245
AN XY:
36568
show subpopulations
Gnomad AFR exome
AF:
0.00137
Gnomad AMR exome
AF:
0.00192
Gnomad ASJ exome
AF:
0.00279
Gnomad EAS exome
AF:
0.000128
Gnomad SAS exome
AF:
0.000499
Gnomad FIN exome
AF:
0.00417
Gnomad NFE exome
AF:
0.0142
Gnomad OTH exome
AF:
0.00424
GnomAD4 exome
AF:
0.0127
AC:
13273
AN:
1042029
Hom.:
76
Cov.:
29
AF XY:
0.0122
AC XY:
4158
AN XY:
341091
show subpopulations
Gnomad4 AFR exome
AF:
0.00173
Gnomad4 AMR exome
AF:
0.00179
Gnomad4 ASJ exome
AF:
0.00220
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000361
Gnomad4 FIN exome
AF:
0.00452
Gnomad4 NFE exome
AF:
0.0153
Gnomad4 OTH exome
AF:
0.0101
GnomAD4 genome
AF:
0.00757
AC:
845
AN:
111660
Hom.:
4
Cov.:
23
AF XY:
0.00659
AC XY:
223
AN XY:
33830
show subpopulations
Gnomad4 AFR
AF:
0.00260
Gnomad4 AMR
AF:
0.00142
Gnomad4 ASJ
AF:
0.00228
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000378
Gnomad4 FIN
AF:
0.00284
Gnomad4 NFE
AF:
0.0135
Gnomad4 OTH
AF:
0.00198
Alfa
AF:
0.00517
Hom.:
44
Bravo
AF:
0.00693
TwinsUK
AF:
0.0138
AC:
51
ALSPAC
AF:
0.0166
AC:
48
ExAC
AF:
0.00229
AC:
38

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Likely benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsApr 24, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.80
T
BayesDel_noAF
Benign
-0.91
CADD
Benign
0.18
DANN
Benign
0.50
DEOGEN2
Benign
0.0038
T
FATHMM_MKL
Benign
0.012
N
LIST_S2
Benign
0.37
T
MetaRNN
Benign
0.0039
T
Sift4G
Benign
0.19
T
Vest4
0.061
MVP
0.13
GERP RS
-4.1

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.

Other links and lift over

dbSNP: rs111428432; hg19: chrX-10469476; API