X-10523193-CAAAAAAAA-C

Variant names:

• chrX-10523193-CAAAAAAAA-C
• rs375668839
• NM_000381.4:c.661-14_661-7delTTTTTTTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000381.4(MID1):​c.661-14_661-7delTTTTTTTT variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000191 in 786,431 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., 1 hem., cov: 19)
  • Exomes 𝑓: 0.000013 (0 hom. 2 hem.)
• Consequence: MID1 NM_000381.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.30
• 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00011 (5/45447) while in subpopulation AFR AF = 0.000195 (3/15351). AF 95% confidence interval is 0.0000526. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MID1	NM_000381.4	c.661-14_661-7delTTTTTTTT		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.661-14_661-7delTTTTTTTT		splice_region_variant, intron_variant	Intron 2 of 9	1	NM_000381.4	ENSP00000312678.4
MID1	ENST00000380782.6	c.661-14_661-7delTTTTTTTT		splice_region_variant, intron_variant	Intron 2 of 9	1		ENSP00000370159.1

Frequencies

GnomAD3 genomes AF: 0.000110 AC: 5 AN: 45447 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.000195

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: 0.0000955

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000135 AC: 10 AN: 740984 Hom.: 0 AF XY: 0.00000970 AC XY: 2 AN XY: 206264

African (AFR) AF: 0.00 AC: 0 AN: 17200

American (AMR) AF: 0.00 AC: 0 AN: 21894

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14747

East Asian (EAS) AF: 0.00 AC: 0 AN: 24955

South Asian (SAS) AF: 0.00 AC: 0 AN: 36746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26859

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2252

European-Non Finnish (NFE) AF: 0.0000178 AC: 10 AN: 562782

Other (OTH) AF: 0.00 AC: 0 AN: 33549

GnomAD4 genome AF: 0.000110 AC: 5 AN: 45447 Hom.: 0 Cov.: 19 AF XY: 0.000111 AC XY: 1 AN XY: 9019

African (AFR) AF: 0.000195 AC: 3 AN: 15351

American (AMR) AF: 0.00 AC: 0 AN: 3450

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: 0.00 AC: 0 AN: 1504

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

European-Non Finnish (NFE) AF: 0.0000955 AC: 2 AN: 20938

Other (OTH) AF: 0.00 AC: 0 AN: 571

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.0000302

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs375668839; hg19: chrX-10491233;