Genetic Variant MID1:c.661-13_661-7delTTTTTTT (chrX-10523193-CAAAAAAA-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BS1

The NM_000381.4(MID1):c.661-13_661-7delTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000636 in 786,412 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000044 ( 0 hom., 0 hem., cov: 19)

Exomes 𝑓: 0.0000040 ( 0 hom. 0 hem. )

Consequence

MID1
NM_000381.4 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.499

Publications

3 publications found

Variant links:

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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

MID1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000044 (2/45447) while in subpopulation NFE AF = 0.0000955 (2/20938). AF 95% confidence interval is 0.0000168. There are 0 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MID1	NM_000381.4 link	c.661-13_661-7delTTTTTTT		splice_region_variant, intron_variant	Intron 2 of 9	ENST00000317552.9	NP_000372.1	O15344-1A0A024RBV4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MID1	ENST00000317552.9 link	c.661-13_661-7delTTTTTTT		splice_region_variant, intron_variant	Intron 2 of 9	1	NM_000381.4	ENSP00000312678.4		O15344-1
MID1	ENST00000380782.6 link	c.661-13_661-7delTTTTTTT		splice_region_variant, intron_variant	Intron 2 of 9	1		ENSP00000370159.1		O15344-2

Frequencies

GnomAD3 genomes

AF:

0.0000440

AC:

AN:

45447

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000955

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000405

AC:

AN:

740965

Hom.:

AF XY:

0.00

AC XY:

AN XY:

206255

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17200

American (AMR)

AF:

0.00

AC:

AN:

21893

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14747

East Asian (EAS)

AF:

0.00

AC:

AN:

24955

South Asian (SAS)

AF:

0.00

AC:

AN:

36746

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26858

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2252

European-Non Finnish (NFE)

AF:

0.00000533

AC:

AN:

562765

Other (OTH)

AF:

0.00

AC:

AN:

33549

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000440

AC:

AN:

45447

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

9019

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

15351

American (AMR)

AF:

0.00

AC:

AN:

3450

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1063

East Asian (EAS)

AF:

0.00

AC:

AN:

1285

South Asian (SAS)

AF:

0.00

AC:

AN:

972

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1504

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0000955

AC:

AN:

20938

Other (OTH)

AF:

0.00

AC:

AN:

571

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.50

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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X-10523193-CAAAAAAAA-CA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over