rs367932687

Variant names:

• chrX-10449394-A-G
• rs367932687
• NM_000381.4:c.1978T>C

Your query was ambiguous. Multiple possible variants found:

• chrX-10449394-A-G
• chrX-10449394-A-C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_000381.4(MID1):​c.1978T>C​(p.Leu660Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000331 in 1,209,442 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: MID1 NM_000381.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.66
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant X-10449394-A-G is Benign according to our data. Variant chrX-10449394-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1904483.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.66 with no splicing effect.

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.1978T>C	p.Leu660Leu	synonymous	Exon 10 of 10	NP_000372.1	O15344-1
	MID1	NM_001098624.2		c.1978T>C	p.Leu660Leu	synonymous	Exon 10 of 10	NP_001092094.1	O15344-1
	MID1	NM_001193277.1		c.1978T>C	p.Leu660Leu	synonymous	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.1978T>C	p.Leu660Leu	synonymous	Exon 10 of 10	ENSP00000312678.4	O15344-1
	MID1	ENST00000380779.5	TSL:1	c.1978T>C	p.Leu660Leu	synonymous	Exon 10 of 10	ENSP00000370156.1	O15344-1
	MID1	ENST00000380780.5	TSL:1	c.1978T>C	p.Leu660Leu	synonymous	Exon 10 of 10	ENSP00000370157.1	O15344-1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111713 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000651

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097729 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363131

African (AFR) AF: 0.0000379 AC: 1 AN: 26392

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

East Asian (EAS) AF: 0.00 AC: 0 AN: 30182

South Asian (SAS) AF: 0.00 AC: 0 AN: 54121

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4073

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841777

Other (OTH) AF: 0.0000217 AC: 1 AN: 46074

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111713 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33923

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000651 AC: 2 AN: 30706

American (AMR) AF: 0.00 AC: 0 AN: 10546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3548

South Asian (SAS) AF: 0.00 AC: 0 AN: 2665

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6020

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53151

Other (OTH) AF: 0.00 AC: 0 AN: 1506

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	8.4
DANN	Benign	0.73
PhyloP100		2.7

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: rs367932687; hg19: chrX-10417434;