NM_000381.4:c.1988C>T

Variant names:

• chrX-10449384-G-A
• rs138558359
• NM_000381.4:c.1988C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_000381.4(MID1):​c.1988C>T​(p.Thr663Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000511 in 1,208,585 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 203 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T663T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., 14 hem., cov: 23)
  • Exomes 𝑓: 0.00053 (0 hom. 189 hem.)
• Consequence: MID1 NM_000381.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.46
• Publications: 1 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.079274535).
• BP6: Variant X-10449384-G-A is Benign according to our data. Variant chrX-10449384-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 92877.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000277 (31/111890) while in subpopulation NFE AF = 0.000488 (26/53235). AF 95% confidence interval is 0.000341. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 14 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.1988C>T	p.Thr663Ile	missense	Exon 10 of 10	NP_000372.1	O15344-1
	MID1	NM_001098624.2		c.1988C>T	p.Thr663Ile	missense	Exon 10 of 10	NP_001092094.1	O15344-1
	MID1	NM_001193277.1		c.1988C>T	p.Thr663Ile	missense	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.1988C>T	p.Thr663Ile	missense	Exon 10 of 10	ENSP00000312678.4	O15344-1
	MID1	ENST00000380779.5	TSL:1	c.1988C>T	p.Thr663Ile	missense	Exon 10 of 10	ENSP00000370156.1	O15344-1
	MID1	ENST00000380780.5	TSL:1	c.1988C>T	p.Thr663Ile	missense	Exon 10 of 10	ENSP00000370157.1	O15344-1

Frequencies

GnomAD3 genomes AF: 0.000277 AC: 31 AN: 111890 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000163

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000488

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000274 AC: 50 AN: 182224 AF XY: 0.000283

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000251

Gnomad NFE exome AF: 0.000555

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.000534 AC: 586 AN: 1096695 Hom.: 0 Cov.: 30 AF XY: 0.000522 AC XY: 189 AN XY: 362183

African (AFR) AF: 0.0000758 AC: 2 AN: 26373

American (AMR) AF: 0.0000284 AC: 1 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19374

East Asian (EAS) AF: 0.00 AC: 0 AN: 30167

South Asian (SAS) AF: 0.00 AC: 0 AN: 54090

European-Finnish (FIN) AF: 0.000222 AC: 9 AN: 40505

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4006

European-Non Finnish (NFE) AF: 0.000659 AC: 554 AN: 840951

Other (OTH) AF: 0.000434 AC: 20 AN: 46030

GnomAD4 genome AF: 0.000277 AC: 31 AN: 111890 Hom.: 0 Cov.: 23 AF XY: 0.000411 AC XY: 14 AN XY: 34042

African (AFR) AF: 0.000163 AC: 5 AN: 30755

American (AMR) AF: 0.00 AC: 0 AN: 10560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3567

South Asian (SAS) AF: 0.00 AC: 0 AN: 2667

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6022

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.000488 AC: 26 AN: 53235

Other (OTH) AF: 0.00 AC: 0 AN: 1508

Alfa AF: 0.000395 Hom.: 15

Bravo AF: 0.000212

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000446 AC: 3

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.000164

EpiControl AF: 0.000357

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	MID1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.5
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.022
Sift	Benign	0.071	T
Sift4G	Benign	0.063	T
Polyphen		0.012	B
Vest4		0.076
MVP		0.51
MPC		0.87
ClinPred		0.052	T
GERP RS		3.4
Varity_R		0.12
gMVP		0.37
Mutation Taster		=100/0	polymorphism

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: rs138558359; hg19: chrX-10417424; COSMIC: COSV106096997; COSMIC: COSV106096997;