6-54124861-G-A

Variant names:

• chr6-54124861-G-A
• rs765867577
• NM_001281747.2:c.641G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001281747.2(MLIP):​c.641G>A​(p.Gly214Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000351 in 1,425,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G214W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: MLIP NM_001281747.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.274
• Publications: 0 publications found

Genes affected

MLIP (HGNC:21355): (muscular LMNA interacting protein) Predicted to enable lamin binding activity and transcription corepressor activity. Predicted to be involved in negative regulation of cardiac muscle hypertrophy in response to stress; negative regulation of transcription by RNA polymerase II; and positive regulation of transcription by RNA polymerase II. Predicted to be located in nuclear lumen. Predicted to be active in PML body; nuclear envelope; and sarcolemma. [provided by Alliance of Genome Resources, Apr 2022]

MLIP Gene-Disease associations (from GenCC):

• myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06550923).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001281747.2. 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
	MLIP	NM_001281747.2	MANE Select	c.641G>A	p.Gly214Glu	missense	Exon 3 of 14	NP_001268676.1	Q5VWP3-3
	MLIP	NM_001281746.2		c.608G>A	p.Gly203Glu	missense	Exon 3 of 12	NP_001268675.1	Q5VWP3-4
	MLIP	NM_138569.3		c.608G>A	p.Gly203Glu	missense	Exon 3 of 13	NP_612636.2	Q5VWP3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLIP	ENST00000502396.6	TSL:2 MANE Select	c.641G>A	p.Gly214Glu	missense	Exon 3 of 14	ENSP00000426290.1	Q5VWP3-3
	MLIP	ENST00000514921.5	TSL:1	c.608G>A	p.Gly203Glu	missense	Exon 3 of 12	ENSP00000425142.1	Q5VWP3-4
	MLIP	ENST00000370876.6	TSL:1	c.422G>A	p.Gly141Glu	missense	Exon 2 of 7	ENSP00000359913.2	Q5VWP3-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000271 AC: 6 AN: 221514 AF XY: 0.0000336

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000350

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000351 AC: 5 AN: 1425900 Hom.: 0 Cov.: 33 AF XY: 0.00000283 AC XY: 2 AN XY: 706188

African (AFR) AF: 0.0000313 AC: 1 AN: 31916

American (AMR) AF: 0.00 AC: 0 AN: 38886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23896

East Asian (EAS) AF: 0.000102 AC: 4 AN: 39368

South Asian (SAS) AF: 0.00 AC: 0 AN: 80140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5518

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095250

Other (OTH) AF: 0.00 AC: 0 AN: 58650

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.050	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.27
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.12
Sift	Benign	0.065	T
Sift4G	Uncertain	0.059	T
Polyphen		0.17	B
Vest4		0.39
MutPred		0.20		Gain of helix (P = 0.0225)
MVP		0.32
MPC		0.039
ClinPred		0.28	T
GERP RS		1.4
Varity_R		0.10
gMVP		0.061
Mutation Taster		=88/12	polymorphism

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: rs765867577; hg19: chr6-53989659; COSMIC: COSV99229369; COSMIC: COSV99229369;