NM_000381.4:c.661-9_661-7delTTT

Variant names:

• chrX-10523193-CAAA-C
• rs375668839
• NM_000381.4:c.661-9_661-7delTTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_000381.4(MID1):​c.661-9_661-7delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 764,370 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., 0 hem., cov: 19)
  • Exomes 𝑓: 0.0039 (0 hom. 0 hem.)
• Consequence: MID1 NM_000381.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.117
• 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MID1	NM_000381.4	c.661-9_661-7delTTT		splice_region_variant, intron_variant	Intron 2 of 9	ENST00000317552.9	NP_000372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MID1	ENST00000317552.9	c.661-9_661-7delTTT		splice_region_variant, intron_variant	Intron 2 of 9	1	NM_000381.4	ENSP00000312678.4
MID1	ENST00000380782.6	c.661-9_661-7delTTT		splice_region_variant, intron_variant	Intron 2 of 9	1		ENSP00000370159.1

Frequencies

GnomAD3 genomes AF: 0.0000660 AC: 3 AN: 45426 Hom.: 0 Cov.: 19

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: 0.00200

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00574 AC: 255 AN: 44423 AF XY: 0.00

Gnomad AFR exome AF: 0.00126

Gnomad AMR exome AF: 0.0104

Gnomad ASJ exome AF: 0.00311

Gnomad EAS exome AF: 0.00653

Gnomad FIN exome AF: 0.00709

Gnomad NFE exome AF: 0.00497

Gnomad OTH exome AF: 0.00572

GnomAD4 exome AF: 0.00386 AC: 2772 AN: 718944 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 197100

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

African (AFR) AF: 0.00374 AC: 63 AN: 16855

American (AMR) AF: 0.00385 AC: 81 AN: 21059

Ashkenazi Jewish (ASJ) AF: 0.00217 AC: 31 AN: 14268

East Asian (EAS) AF: 0.00149 AC: 36 AN: 24085

South Asian (SAS) AF: 0.00159 AC: 56 AN: 35132

European-Finnish (FIN) AF: 0.00143 AC: 37 AN: 25956

Middle Eastern (MID) AF: 0.00321 AC: 7 AN: 2180

European-Non Finnish (NFE) AF: 0.00430 AC: 2350 AN: 546892

Other (OTH) AF: 0.00341 AC: 111 AN: 32517

⚠️ 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: 0.0000660 AC: 3 AN: 45426 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 9014

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

African (AFR) AF: 0.00 AC: 0 AN: 15351

American (AMR) AF: 0.00 AC: 0 AN: 3448

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1063

East Asian (EAS) AF: 0.00 AC: 0 AN: 1285

South Asian (SAS) AF: 0.00 AC: 0 AN: 972

European-Finnish (FIN) AF: 0.00200 AC: 3 AN: 1500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 59

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 20925

Other (OTH) AF: 0.00 AC: 0 AN: 569

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00497 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.12
Mutation Taster		=100/0	polymorphism

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;