rs1556001939

Positions:

• chrX-10449607-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000381.4(MID1):​c.1765A>G​(p.Asn589Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000546 in 1,098,071 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 2 hem.)
• Consequence: MID1 NM_000381.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.77

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24026412).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MID1	NM_000381.4	c.1765A>G	p.Asn589Asp	missense_variant	10/10	ENST00000317552.9	NP_000372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MID1	ENST00000317552.9	c.1765A>G	p.Asn589Asp	missense_variant	10/10	1	NM_000381.4	ENSP00000312678	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000546 AC: 6 AN: 1098071 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 2 AN XY: 363441

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000594

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertelorism;C0175754:Corpus callosum, agenesis of;C0239234:Low-set ears;C0424503:Abnormal facial shape;C1850049:Clinodactyly of the 5th finger Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T;T;T;T;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T;.;.;.;.;.
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.24	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.79	N;N;N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.96	N;N;N;N;N;N
REVEL	Benign	0.066
Sift	Benign	0.32	T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;B
Vest4		0.33
MVP		0.72
MPC		0.91
ClinPred		0.33	T
GERP RS		4.3
Varity_R		0.33
gMVP		0.82

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: rs1556001939; hg19: chrX-10417647;