rs7391874

Variant names:

• chrX-10567050-C-T
• rs7391874
• NM_000381.4:c.498G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000381.4(MID1):​c.498G>A​(p.Pro166Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,209,747 control chromosomes in the GnomAD database, including 60 homozygotes. There are 713 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (5 hom., 144 hem., cov: 22)
  • Exomes 𝑓: 0.0021 (55 hom. 569 hem.)
• Consequence: MID1 NM_000381.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.37
• 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: Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000291314 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant X-10567050-C-T is Benign according to our data. Variant chrX-10567050-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.37 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0515 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MID1	NM_000381.4	MANE Select	c.498G>A	p.Pro166Pro	synonymous	Exon 2 of 10	NP_000372.1	O15344-1
	MID1	NM_001098624.2		c.498G>A	p.Pro166Pro	synonymous	Exon 2 of 10	NP_001092094.1	O15344-1
	MID1	NM_001193277.1		c.498G>A	p.Pro166Pro	synonymous	Exon 2 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.498G>A	p.Pro166Pro	synonymous	Exon 2 of 10	ENSP00000312678.4	O15344-1
	MID1	ENST00000380779.5	TSL:1	c.498G>A	p.Pro166Pro	synonymous	Exon 2 of 10	ENSP00000370156.1	O15344-1
	MID1	ENST00000380780.5	TSL:1	c.498G>A	p.Pro166Pro	synonymous	Exon 2 of 10	ENSP00000370157.1	O15344-1

Frequencies

GnomAD3 genomes AF: 0.00376 AC: 419 AN: 111454 Hom.: 5 Cov.: 22

Gnomad AFR AF: 0.00105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00763

Gnomad SAS AF: 0.000758

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.00467

GnomAD2 exomes AF: 0.00974 AC: 1786 AN: 183366 AF XY: 0.00630

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.0598

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00577

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000122

Gnomad OTH exome AF: 0.00795

GnomAD4 exome AF: 0.00209 AC: 2290 AN: 1098240 Hom.: 55 Cov.: 32 AF XY: 0.00156 AC XY: 569 AN XY: 363594

African (AFR) AF: 0.000606 AC: 16 AN: 26403

American (AMR) AF: 0.0535 AC: 1883 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00358 AC: 108 AN: 30206

South Asian (SAS) AF: 0.000240 AC: 13 AN: 54148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40529

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.000180 AC: 152 AN: 842134

Other (OTH) AF: 0.00256 AC: 118 AN: 46097

GnomAD4 genome AF: 0.00378 AC: 422 AN: 111507 Hom.: 5 Cov.: 22 AF XY: 0.00427 AC XY: 144 AN XY: 33717

African (AFR) AF: 0.00104 AC: 32 AN: 30625

American (AMR) AF: 0.0330 AC: 348 AN: 10542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00766 AC: 27 AN: 3526

South Asian (SAS) AF: 0.000760 AC: 2 AN: 2631

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6053

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000113 AC: 6 AN: 53067

Other (OTH) AF: 0.00461 AC: 7 AN: 1518

Alfa AF: 0.00135 Hom.: 5

Bravo AF: 0.00638

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	MID1-related disorder (1)
-	-	1	X-linked Opitz G/BBB syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	6.5
DANN	Benign	0.76
PhyloP100		-1.4
PromoterAI		-0.023	Neutral
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: rs7391874; hg19: chrX-10535090;