chrX-10469716-G-A

Variant names:

• chrX-10469716-G-A
• rs148477118
• NM_000381.4:c.1266C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000381.4(MID1):​c.1266C>T​(p.Thr422Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,209,683 control chromosomes in the GnomAD database, including 15 homozygotes. There are 461 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T422T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (3 hom., 31 hem., cov: 23)
  • Exomes 𝑓: 0.0012 (12 hom. 430 hem.)
• Consequence: MID1 NM_000381.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.255
• 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, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant X-10469716-G-A is Benign according to our data. Variant chrX-10469716-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.255 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00142 (159/111946) while in subpopulation NFE AF = 0.000545 (29/53225). AF 95% confidence interval is 0.00039. There are 3 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 XL gene

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.1266C>T	p.Thr422Thr	synonymous	Exon 7 of 10	NP_000372.1	O15344-1
	MID1	NM_001098624.2		c.1266C>T	p.Thr422Thr	synonymous	Exon 7 of 10	NP_001092094.1	O15344-1
	MID1	NM_001193277.1		c.1266C>T	p.Thr422Thr	synonymous	Exon 7 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.1266C>T	p.Thr422Thr	synonymous	Exon 7 of 10	ENSP00000312678.4	O15344-1
	MID1	ENST00000380779.5	TSL:1	c.1266C>T	p.Thr422Thr	synonymous	Exon 7 of 10	ENSP00000370156.1	O15344-1
	MID1	ENST00000380780.5	TSL:1	c.1266C>T	p.Thr422Thr	synonymous	Exon 7 of 10	ENSP00000370157.1	O15344-1

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 159 AN: 111893 Hom.: 3 Cov.: 23

Gnomad AFR AF: 0.0000650

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0463

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000545

Gnomad OTH AF: 0.00331

GnomAD2 exomes AF: 0.00236 AC: 432 AN: 182817 AF XY: 0.00209

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.0468

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000762

Gnomad OTH exome AF: 0.00355

GnomAD4 exome AF: 0.00121 AC: 1324 AN: 1097737 Hom.: 12 Cov.: 31 AF XY: 0.00118 AC XY: 430 AN XY: 363175

African (AFR) AF: 0.0000758 AC: 2 AN: 26385

American (AMR) AF: 0.000114 AC: 4 AN: 35188

Ashkenazi Jewish (ASJ) AF: 0.0461 AC: 893 AN: 19379

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.0000554 AC: 3 AN: 54128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40525

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4134

European-Non Finnish (NFE) AF: 0.000321 AC: 270 AN: 841718

Other (OTH) AF: 0.00328 AC: 151 AN: 46081

GnomAD4 genome AF: 0.00142 AC: 159 AN: 111946 Hom.: 3 Cov.: 23 AF XY: 0.000908 AC XY: 31 AN XY: 34132

African (AFR) AF: 0.0000649 AC: 2 AN: 30824

American (AMR) AF: 0.00 AC: 0 AN: 10527

Ashkenazi Jewish (ASJ) AF: 0.0463 AC: 123 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3542

South Asian (SAS) AF: 0.00 AC: 0 AN: 2657

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6079

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.000545 AC: 29 AN: 53225

Other (OTH) AF: 0.00327 AC: 5 AN: 1530

Alfa AF: 0.00642 Hom.: 35

Bravo AF: 0.00149

EpiCase AF: 0.000819

EpiControl AF: 0.00160

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	1.1
DANN	Benign	0.79
PhyloP100		-0.26
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: rs148477118; hg19: chrX-10437756;