X-10449389-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP4_Moderate BP6_Moderate BS2

The NM_000381.4(MID1):c.1983C>G(p.Asp661Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000893 in 111,953 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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 Benign (★). Synonymous variant affecting the same amino acid position (i.e. D661D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 2 hem.)
  • Failed GnomAD Quality Control
• Consequence: MID1 NM_000381.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.73

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07843447).
• BP6: Variant X-10449389-G-C is Benign according to our data. Variant chrX-10449389-G-C is described in ClinVar as [Benign]. Clinvar id is 2895424.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MID1	NM_000381.4	c.1983C>G	p.Asp661Glu	missense_variant	10/10	ENST00000317552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MID1	ENST00000317552.9	c.1983C>G	p.Asp661Glu	missense_variant	10/10	1	NM_000381.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111905 Hom.: 0 Cov.: 23 AF XY: 0.0000294 AC XY: 1 AN XY: 34067

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000374

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000110 AC: 2 AN: 182525 Hom.: 0 AF XY: 0.0000297 AC XY: 2 AN XY: 67281

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: 0.000105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000182 AC: 2 AN: 1097246 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 2 AN XY: 362678

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000370

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 111953 Hom.: 0 Cov.: 23 AF XY: 0.0000293 AC XY: 1 AN XY: 34125

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000375

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.80
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.19	T;T;T;T;T;T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.79	T;.;.;.;.;.
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.078	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.55	N;N;N;N;N;N
MutationTaster	Benign	0.89	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.31	N;N;N;N;N;N
REVEL	Benign	0.075
Sift	Benign	0.17	T;T;T;T;T;T
Sift4G	Benign	0.54	T;T;T;T;T;T
Polyphen		0.0040	B;B;B;B;B;B
Vest4		0.036
MutPred		0.30		Gain of disorder (P = 0.1354);Gain of disorder (P = 0.1354);Gain of disorder (P = 0.1354);Gain of disorder (P = 0.1354);Gain of disorder (P = 0.1354);Gain of disorder (P = 0.1354);
MVP		0.70
MPC		0.76
ClinPred		0.27	T
GERP RS		3.7
Varity_R		0.26
gMVP		0.34

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: rs767075372; hg19: chrX-10417429;