chrX-10501436-C-T

Variant names:

• chrX-10501436-C-T
• rs111428432
• ENST00000616003.5:c.880G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001193278.1(MID1):​c.880G>A​(p.Glu294Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,153,689 control chromosomes in the GnomAD database, including 80 homozygotes. There are 4,381 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 9/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (4 hom., 223 hem., cov: 23)
  • Exomes 𝑓: 0.013 (76 hom. 4158 hem.)
• Consequence: MID1 NM_001193278.1 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.61
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039096773).
• BP6: Variant X-10501436-C-T is Benign according to our data. Variant chrX-10501436-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 445919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00757 (845/111660) while in subpopulation NFE AF = 0.0135 (715/53136). AF 95% confidence interval is 0.0126. There are 4 homozygotes in GnomAd4. There are 223 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001193278.1. 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.757-5745G>A		intron	N/A	NP_000372.1
	MID1	NM_001193278.1		c.880G>A	p.Glu294Lys	missense	Exon 3 of 7	NP_001180207.1
	MID1	NM_001098624.2		c.757-5745G>A		intron	N/A	NP_001092094.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MID1	ENST00000616003.5	TSL:1	c.880G>A	p.Glu294Lys	missense	Exon 3 of 7	ENSP00000484712.1
	MID1	ENST00000317552.9	TSL:1 MANE Select	c.757-5745G>A		intron	N/A	ENSP00000312678.4
	MID1	ENST00000380779.5	TSL:1	c.757-5745G>A		intron	N/A	ENSP00000370156.1

Frequencies

GnomAD3 genomes AF: 0.00758 AC: 846 AN: 111607 Hom.: 4 Cov.: 23

Gnomad AFR AF: 0.00260

Gnomad AMI AF: 0.0118

Gnomad AMR AF: 0.00143

Gnomad ASJ AF: 0.00228

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000377

Gnomad FIN AF: 0.00284

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.00268

GnomAD2 exomes AF: 0.00659 AC: 645 AN: 97874 AF XY: 0.00670

Gnomad AFR exome AF: 0.00137

Gnomad AMR exome AF: 0.00192

Gnomad ASJ exome AF: 0.00279

Gnomad EAS exome AF: 0.000128

Gnomad FIN exome AF: 0.00417

Gnomad NFE exome AF: 0.0142

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.0127 AC: 13273 AN: 1042029 Hom.: 76 Cov.: 29 AF XY: 0.0122 AC XY: 4158 AN XY: 341091

African (AFR) AF: 0.00173 AC: 43 AN: 24912

American (AMR) AF: 0.00179 AC: 50 AN: 27908

Ashkenazi Jewish (ASJ) AF: 0.00220 AC: 41 AN: 18642

East Asian (EAS) AF: 0.00 AC: 0 AN: 27131

South Asian (SAS) AF: 0.000361 AC: 18 AN: 49872

European-Finnish (FIN) AF: 0.00452 AC: 117 AN: 25904

Middle Eastern (MID) AF: 0.000734 AC: 3 AN: 4087

European-Non Finnish (NFE) AF: 0.0153 AC: 12554 AN: 819271

Other (OTH) AF: 0.0101 AC: 447 AN: 44302

GnomAD4 genome AF: 0.00757 AC: 845 AN: 111660 Hom.: 4 Cov.: 23 AF XY: 0.00659 AC XY: 223 AN XY: 33830

African (AFR) AF: 0.00260 AC: 80 AN: 30787

American (AMR) AF: 0.00142 AC: 15 AN: 10528

Ashkenazi Jewish (ASJ) AF: 0.00228 AC: 6 AN: 2637

East Asian (EAS) AF: 0.00 AC: 0 AN: 3535

South Asian (SAS) AF: 0.000378 AC: 1 AN: 2643

European-Finnish (FIN) AF: 0.00284 AC: 17 AN: 5985

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0135 AC: 715 AN: 53136

Other (OTH) AF: 0.00198 AC: 3 AN: 1513

Alfa AF: 0.00417 Hom.: 52

Bravo AF: 0.00693

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.0166 AC: 48

ExAC AF: 0.00229 AC: 38

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
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.18
DANN	Benign	0.50
DEOGEN2	Benign	0.0038	T
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0039	T
PhyloP100		-1.6
Sift4G	Benign	0.19	T
Vest4		0.061
MVP		0.13
GERP RS		-4.1
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: rs111428432; hg19: chrX-10469476;