rs764985543

Variant names:

• chrX-10449371-C-T
• rs764985543
• NM_000381.4:c.2001G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 2P and 17B. PM2 BP4_Strong BP6_Very_Strong BP7 BS1

The NM_000381.4(MID1):​c.2001G>A​(p.Pro667Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000366 in 1,093,323 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000037 (0 hom. 0 hem.)
• Consequence: MID1 NM_000381.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.63
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant X-10449371-C-T is Benign according to our data. Variant chrX-10449371-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 916504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.63 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.00000366 (4/1093323) while in subpopulation AFR AF = 0.000114 (3/26310). AF 95% confidence interval is 0.0000302. There are 0 homozygotes in GnomAdExome4. There are 0 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MID1	NM_000381.4	MANE Select	c.2001G>A	p.Pro667Pro	synonymous	Exon 10 of 10	NP_000372.1	O15344-1
	MID1	NM_001098624.2		c.2001G>A	p.Pro667Pro	synonymous	Exon 10 of 10	NP_001092094.1	O15344-1
	MID1	NM_001193277.1		c.2001G>A	p.Pro667Pro	synonymous	Exon 10 of 10	NP_001180206.1	O15344-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MID1	ENST00000317552.9	TSL:1 MANE Select	c.2001G>A	p.Pro667Pro	synonymous	Exon 10 of 10	ENSP00000312678.4	O15344-1
	MID1	ENST00000380779.5	TSL:1	c.2001G>A	p.Pro667Pro	synonymous	Exon 10 of 10	ENSP00000370156.1	O15344-1
	MID1	ENST00000380780.5	TSL:1	c.2001G>A	p.Pro667Pro	synonymous	Exon 10 of 10	ENSP00000370157.1	O15344-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000166 AC: 3 AN: 180711 AF XY: 0.00

Gnomad AFR exome AF: 0.000235

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000366 AC: 4 AN: 1093323 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 359151

African (AFR) AF: 0.000114 AC: 3 AN: 26310

American (AMR) AF: 0.00 AC: 0 AN: 35164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19352

East Asian (EAS) AF: 0.00 AC: 0 AN: 30146

South Asian (SAS) AF: 0.00 AC: 0 AN: 53963

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40397

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3861

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 838216

Other (OTH) AF: 0.00 AC: 0 AN: 45914

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.015
DANN	Benign	0.46
PhyloP100		-2.6

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: rs764985543; hg19: chrX-10417411;