chrX-10523193-CAAAA-C

Variant names:

• chrX-10523193-CAAAA-C
• rs375668839
• NM_000381.4:c.661-10_661-7delTTTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000381.4(MID1):​c.661-10_661-7delTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0009 in 777,779 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes 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 0.00011 (0 hom., 0 hem., cov: 19)
  • Exomes 𝑓: 0.00095 (0 hom. 8 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MID1	NM_000381.4	c.661-10_661-7delTTTT		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.661-10_661-7delTTTT		splice_region_variant, intron_variant	Intron 2 of 9	1	NM_000381.4	ENSP00000312678.4
MID1	ENST00000380782.6	c.661-10_661-7delTTTT		splice_region_variant, intron_variant	Intron 2 of 9	1		ENSP00000370159.1

Frequencies

GnomAD3 genomes AF: 0.000110 AC: 5 AN: 45436 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: 0.00133

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000143

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000949 AC: 695 AN: 732343 Hom.: 0 AF XY: 0.0000395 AC XY: 8 AN XY: 202537

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

African (AFR) AF: 0.00111 AC: 19 AN: 17066

American (AMR) AF: 0.00111 AC: 24 AN: 21591

Ashkenazi Jewish (ASJ) AF: 0.000482 AC: 7 AN: 14530

East Asian (EAS) AF: 0.000162 AC: 4 AN: 24701

South Asian (SAS) AF: 0.000194 AC: 7 AN: 36128

European-Finnish (FIN) AF: 0.000490 AC: 13 AN: 26533

Middle Eastern (MID) AF: 0.000901 AC: 2 AN: 2220

European-Non Finnish (NFE) AF: 0.00105 AC: 586 AN: 556409

Other (OTH) AF: 0.000995 AC: 33 AN: 33165

⚠️ 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: 0.000110 AC: 5 AN: 45436 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: 3445

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: 0.00133 AC: 2 AN: 1503

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

European-Non Finnish (NFE) AF: 0.000143 AC: 3 AN: 20933

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0146308), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000425 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.12

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;