16-20915595-C-T

Variant names:

• chr16-20915595-C-T
• rs149175521
• NM_001128302.3:c.40C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001128302.3(LYRM1):​c.40C>T​(p.Arg14Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000436 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00044 (0 hom.)
• Consequence: LYRM1 NM_001128302.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.36
• Publications: 7 publications found

Genes affected

LYRM1 (HGNC:25074): (LYR motif containing 1) The protein encoded by this gene belongs to the mitochondrial leucine/tyrosine/arginine motif family of proteins. Proteins of this family are short polypeptides that contain a leucine/tyrosine/arginine motif near the N-terminus. This gene is widely expressed with high levels in omental adipose tissue of obese individuals. In adipose tissue, the protein is localized to the nucleus where it promotes preadipocyte proliferation and lowers the rate of apoptosis to regulate adipose tissue homeostasis. Overexpression of this gene in adipocytes causes abnormal mitochondrial morphology and mitochondrial dysfunction. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128302.3. 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
	LYRM1	NM_001128302.3	MANE Select	c.40C>T	p.Arg14Cys	missense	Exon 2 of 4	NP_001121774.1	O43325
	LYRM1	NM_001369631.1		c.40C>T	p.Arg14Cys	missense	Exon 3 of 6	NP_001356560.1
	LYRM1	NM_001128301.3		c.40C>T	p.Arg14Cys	missense	Exon 3 of 5	NP_001121773.1	O43325

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYRM1	ENST00000567954.6	TSL:1 MANE Select	c.40C>T	p.Arg14Cys	missense	Exon 2 of 4	ENSP00000457333.1	O43325
	LYRM1	ENST00000396052.3	TSL:1	c.40C>T	p.Arg14Cys	missense	Exon 4 of 6	ENSP00000379367.2	O43325
	LYRM1	ENST00000412082.6	TSL:1	c.-108-4527C>T		intron	N/A	ENSP00000396868.2	H3BNA8

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152078 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000169

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: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000183 AC: 46 AN: 251472 AF XY: 0.000177

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000441 AC: 644 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.000415 AC XY: 302 AN XY: 727230

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.000168 AC: 9 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000537 AC: 597 AN: 1111990

Other (OTH) AF: 0.000546 AC: 33 AN: 60396

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152194 Hom.: 0 Cov.: 31 AF XY: 0.000349 AC XY: 26 AN XY: 74406

African (AFR) AF: 0.000169 AC: 7 AN: 41542

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 68014

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.000386 Hom.: 0

Bravo AF: 0.000325

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.000545

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		5.4
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.95
MVP		0.93
MPC		0.37
ClinPred		0.78	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.69
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149175521; hg19: chr16-20926917; COSMIC: COSV54643513;