X-10501436-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000616003.5(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. 9/10 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
ENST00000616003.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.61

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

X-linked Opitz G/BBB syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

MID1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 445919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MID1	NM_000381.4 link	c.757-5745G>A		intron_variant	Intron 3 of 9	ENST00000317552.9	NP_000372.1	O15344-1A0A024RBV4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MID1	ENST00000317552.9 link	c.757-5745G>A		intron_variant	Intron 3 of 9	1	NM_000381.4	ENSP00000312678.4		O15344-1
MID1	ENST00000380782.6 link	c.757-5745G>A		intron_variant	Intron 3 of 9	1		ENSP00000370159.1		O15344-2

Frequencies

GnomAD3 genomes

AF:

0.00758

AC:

846

AN:

111607

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00659

AC:

645

AN:

97874

AF XY:

0.00670

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 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.:

Cov.:

AF XY:

0.0122

AC XY:

4158

AN XY:

341091

show subpopulations

African (AFR)

AF:

0.00173

AC:

AN:

24912

American (AMR)

AF:

0.00179

AC:

AN:

27908

Ashkenazi Jewish (ASJ)

AF:

0.00220

AC:

AN:

18642

East Asian (EAS)

AF:

0.00

AC:

AN:

27131

South Asian (SAS)

AF:

0.000361

AC:

AN:

49872

European-Finnish (FIN)

AF:

0.00452

AC:

117

AN:

25904

Middle Eastern (MID)

AF:

0.000734

AC:

AN:

4087

European-Non Finnish (NFE)

AF:

0.0153

AC:

12554

AN:

819271

Other (OTH)

AF:

0.0101

AC:

447

AN:

44302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

429

857

1286

1714

2143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

480

960

1440

1920

2400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00757

AC:

845

AN:

111660

Hom.:

Cov.:

AF XY:

0.00659

AC XY:

223

AN XY:

33830

show subpopulations

African (AFR)

AF:

0.00260

AC:

AN:

30787

American (AMR)

AF:

0.00142

AC:

AN:

10528

Ashkenazi Jewish (ASJ)

AF:

0.00228

AC:

AN:

2637

East Asian (EAS)

AF:

0.00

AC:

AN:

3535

South Asian (SAS)

AF:

0.000378

AC:

AN:

2643

European-Finnish (FIN)

AF:

0.00284

AC:

AN:

5985

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0135

AC:

715

AN:

53136

Other (OTH)

AF:

0.00198

AC:

AN:

1513

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

100

134

167

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00417

Hom.:

Bravo

AF:

0.00693

TwinsUK

AF:

0.0138

AC:

ALSPAC

AF:

0.0166

AC:

ExAC

AF:

0.00229

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 24, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.18

(source)

DANN

Benign

0.50

DEOGEN2

Benign

0.0038

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.37

MetaRNN

Benign

0.0039

PhyloP100

-1.6

Sift4G

Benign

0.19

Vest4

0.061

MVP

0.13

GERP RS

-4.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over