X-10449384-G-A

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 92877.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=2}. Variant chrX-10449384-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MID1	NM_000381.4	c.1988C>T	p.Thr663Ile	missense_variant	10/10	ENST00000317552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MID1	ENST00000317552.9	c.1988C>T	p.Thr663Ile	missense_variant	10/10	1	NM_000381.4	P1

Frequencies

GnomAD3 genomes AF: 0.000277 AC: 31 AN: 111890 Hom.: 0 Cov.: 23 AF XY: 0.000411 AC XY: 14 AN XY: 34042

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

GnomAD3 exomes AF: 0.000274 AC: 50 AN: 182224 Hom.: 0 AF XY: 0.000283 AC XY: 19 AN XY: 67050

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 SAS 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

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000222

Gnomad4 NFE exome AF: 0.000659

Gnomad4 OTH exome AF: 0.000434

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

Gnomad4 AFR AF: 0.000163

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000488

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000423 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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

MID1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 08, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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;T;T;T;T;T
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.80	T;.;.;.;.;.
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.079	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L;L;L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N
REVEL	Benign	0.022
Sift	Benign	0.071	T;T;T;T;T;T
Sift4G	Benign	0.063	T;T;T;T;T;T
Polyphen		0.012	B;B;B;B;B;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs138558359; hg19: chrX-10417424;