rs147106995

chrX-10449372-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000381.4(MID1):c.2000C>T(p.Pro667Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00142 in 1,205,410 control chromosomes in the GnomAD database, including 14 homozygotes. There are 525 hemizygotes in GnomAD. In-silico tool predicts 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. P667P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., 112 hem., cov: 23)
  • Exomes 𝑓: 0.0013 (12 hom. 413 hem.)
• Consequence: MID1 NM_000381.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 4.45

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066638887).
• BP6: Variant X-10449372-G-A is Benign according to our data. Variant chrX-10449372-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 92878.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=1, Uncertain_significance=1}. Variant chrX-10449372-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00266 (297/111682) while in subpopulation AMR AF= 0.022 (232/10531). AF 95% confidence interval is 0.0197. There are 2 homozygotes in gnomad4. There are 112 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MID1	NM_000381.4	c.2000C>T	p.Pro667Leu	missense_variant	10/10	ENST00000317552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MID1	ENST00000317552.9	c.2000C>T	p.Pro667Leu	missense_variant	10/10	1	NM_000381.4	P1

Frequencies

GnomAD3 genomes AF: 0.00266 AC: 297 AN: 111632 Hom.: 2 Cov.: 23 AF XY: 0.00331 AC XY: 112 AN XY: 33816

Gnomad AFR AF: 0.000293

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0221

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.000754

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000941

Gnomad OTH AF: 0.00596

GnomAD3 exomes AF: 0.00556 AC: 1006 AN: 180978 Hom.: 9 AF XY: 0.00425 AC XY: 281 AN XY: 66126

Gnomad AFR exome AF: 0.000466

Gnomad AMR exome AF: 0.0305

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0104

Gnomad SAS exome AF: 0.0000529

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000745

Gnomad OTH exome AF: 0.00427

GnomAD4 exome AF: 0.00129 AC: 1409 AN: 1093728 Hom.: 12 Cov.: 29 AF XY: 0.00115 AC XY: 413 AN XY: 359500

Gnomad4 AFR exome AF: 0.000342

Gnomad4 AMR exome AF: 0.0308

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00610

Gnomad4 SAS exome AF: 0.000315

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.0000465

Gnomad4 OTH exome AF: 0.00163

GnomAD4 genome AF: 0.00266 AC: 297 AN: 111682 Hom.: 2 Cov.: 23 AF XY: 0.00331 AC XY: 112 AN XY: 33876

Gnomad4 AFR AF: 0.000293

Gnomad4 AMR AF: 0.0220

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0113

Gnomad4 SAS AF: 0.000757

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000941

Gnomad4 OTH AF: 0.00589

Alfa AF: 0.000800 Hom.: 25

Bravo AF: 0.00432

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00383 AC: 465

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

X-linked Opitz G/BBB syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 07, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 16, 2013	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	MID1: BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 14, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T;T;T;T;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D;.;.;.;.;.
MetaRNN	Benign	0.0067	T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.69	N;N;N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.0	N;N;N;N;N;N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.34
MVP		0.58
MPC		1.9
ClinPred		0.058	T
GERP RS		4.8
Varity_R		0.22
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs147106995; hg19: chrX-10417412;