NM_000381.4:c.1937A>G

Variant names:

• chrX-10449435-T-C
• rs757315836
• NM_000381.4:c.1937A>G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_000381.4(MID1):​c.1937A>G​(p.Lys646Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,098,175 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000012 (0 hom. 2 hem.)
• Consequence: MID1 NM_000381.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.69

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.293486).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MID1	NM_000381.4	c.1937A>G	p.Lys646Arg	missense_variant	Exon 10 of 10	ENST00000317552.9	NP_000372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MID1	ENST00000317552.9	c.1937A>G	p.Lys646Arg	missense_variant	Exon 10 of 10	1	NM_000381.4	ENSP00000312678.4
MID1	ENST00000380782	c.*178A>G		3_prime_UTR_variant	Exon 10 of 10	1		ENSP00000370159.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000547 AC: 1 AN: 182972 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67624

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000118 AC: 13 AN: 1098175 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 2 AN XY: 363539

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000154

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 19, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T;T;T;T;T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D;.;.;.;.;.
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.29	T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.3	L;L;L;L;L;L
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.88	N;N;N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.092	T;T;T;T;T;T
Sift4G	Benign	0.49	T;T;T;T;T;T
Polyphen		0.011	B;B;B;B;B;B
Vest4		0.091
MutPred		0.51		Loss of methylation at K646 (P = 4e-04);Loss of methylation at K646 (P = 4e-04);Loss of methylation at K646 (P = 4e-04);Loss of methylation at K646 (P = 4e-04);Loss of methylation at K646 (P = 4e-04);Loss of methylation at K646 (P = 4e-04);
MVP		0.80
MPC		0.75
ClinPred		0.32	T
GERP RS		5.5
Varity_R		0.60
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs757315836; hg19: chrX-10417475;