NM_000381.4:c.661-7dupT

Variant names:

• chrX-10523193-C-CA
• rs375668839
• NM_000381.4:c.661-7dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000381.4(MID1):​c.661-7dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (127 hom., 533 hem., cov: 19)
  • Exomes 𝑓: 0.099 (7 hom. 96 hem.)
• Consequence: MID1 NM_000381.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.00
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant X-10523193-C-CA is Benign according to our data. Variant chrX-10523193-C-CA is described in ClinVar as Benign. ClinVar VariationId is 196261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000381.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MID1	NM_000381.4	MANE Select	c.661-7dupT		splice_region intron	N/A	NP_000372.1
	MID1	NM_001098624.2		c.661-7dupT		splice_region intron	N/A	NP_001092094.1
	MID1	NM_001193277.1		c.661-7dupT		splice_region intron	N/A	NP_001180206.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MID1	ENST00000317552.9	TSL:1 MANE Select	c.661-7_661-6insT		splice_region intron	N/A	ENSP00000312678.4
	MID1	ENST00000380779.5	TSL:1	c.661-7_661-6insT		splice_region intron	N/A	ENSP00000370156.1
	MID1	ENST00000380780.5	TSL:1	c.661-7_661-6insT		splice_region intron	N/A	ENSP00000370157.1

Frequencies

GnomAD3 genomes AF: 0.0820 AC: 3713 AN: 45300 Hom.: 127 Cov.: 19

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.00394

Gnomad AMR AF: 0.0437

Gnomad ASJ AF: 0.0405

Gnomad EAS AF: 0.0101

Gnomad SAS AF: 0.0556

Gnomad FIN AF: 0.0810

Gnomad MID AF: 0.0508

Gnomad NFE AF: 0.0321

Gnomad OTH AF: 0.0776

GnomAD2 exomes AF: 0.138 AC: 6132 AN: 44423 AF XY: 0.0135

Gnomad AFR exome AF: 0.188

Gnomad AMR exome AF: 0.129

Gnomad ASJ exome AF: 0.153

Gnomad EAS exome AF: 0.166

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.128

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.0987 AC: 65056 AN: 659239 Hom.: 7 Cov.: 0 AF XY: 0.000648 AC XY: 96 AN XY: 148087

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.147 AC: 2239 AN: 15282

American (AMR) AF: 0.0819 AC: 1607 AN: 19625

Ashkenazi Jewish (ASJ) AF: 0.0956 AC: 1240 AN: 12975

East Asian (EAS) AF: 0.0889 AC: 1905 AN: 21430

South Asian (SAS) AF: 0.0681 AC: 2034 AN: 29888

European-Finnish (FIN) AF: 0.104 AC: 2436 AN: 23323

Middle Eastern (MID) AF: 0.0890 AC: 175 AN: 1966

European-Non Finnish (NFE) AF: 0.0998 AC: 50416 AN: 504988

Other (OTH) AF: 0.101 AC: 3004 AN: 29762

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0820 AC: 3716 AN: 45299 Hom.: 127 Cov.: 19 AF XY: 0.0594 AC XY: 533 AN XY: 8979

African (AFR) AF: 0.171 AC: 2616 AN: 15318

American (AMR) AF: 0.0437 AC: 150 AN: 3434

Ashkenazi Jewish (ASJ) AF: 0.0405 AC: 43 AN: 1062

East Asian (EAS) AF: 0.0102 AC: 13 AN: 1275

South Asian (SAS) AF: 0.0571 AC: 55 AN: 964

European-Finnish (FIN) AF: 0.0810 AC: 121 AN: 1494

Middle Eastern (MID) AF: 0.0588 AC: 3 AN: 51

European-Non Finnish (NFE) AF: 0.0321 AC: 670 AN: 20874

Other (OTH) AF: 0.0768 AC: 44 AN: 573

Alfa AF: 0.0304 Hom.: 1

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Nov 30, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs375668839; hg19: chrX-10491233;