5-131180118-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_181705.4(LYRM7):c.42G>A(p.Leu14=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0383 in 1,611,338 control chromosomes in the GnomAD database, including 1,436 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (95 hom., cov: 30)
  • Exomes 𝑓: 0.039 (1341 hom.)
• Consequence: LYRM7 NM_181705.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.07

Genes affected

LYRM7 (HGNC:28072): (LYR motif containing 7) Inner mitochondrial membrane complex III (CIII) is the main enzyme complex in the mitochondrial respiratory chain, and Rieske Fe-S protein (UQCRFS1) is the last catalytic subunit added to the complex. The protein encoded by this gene is a nuclear-encoded mitochondrial matrix protein that stabilizes UQCRFS1 and chaperones it to the CIII complex. Defects in this gene are a cause of mitochondrial complex III deficiency, nuclear type 8. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jun 2014]

HINT1 (HGNC:4912): (histidine triad nucleotide binding protein 1) This gene encodes a protein that hydrolyzes purine nucleotide phosphoramidates substrates, including AMP-morpholidate, AMP-N-alanine methyl ester, AMP-alpha-acetyl lysine methyl ester, and AMP-NH2. The encoded protein interacts with these substrates via a histidine triad motif. This gene is considered a tumor suppressor gene. In addition, mutations in this gene can cause autosomal recessive neuromyotonia and axonal neuropathy. There are several related pseudogenes on chromosome 7. Several transcript variants have been observed. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 5-131180118-G-A is Benign according to our data. Variant chr5-131180118-G-A is described in ClinVar as [Benign]. Clinvar id is 380079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-131180118-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0313 (4764/152112) while in subpopulation NFE AF= 0.0456 (3102/68004). AF 95% confidence interval is 0.0443. There are 95 homozygotes in gnomad4. There are 2330 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 95 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LYRM7	NM_181705.4	c.42G>A	p.Leu14=	synonymous_variant	2/5	ENST00000379380.9
LYRM7	NM_001293735.2	c.42G>A	p.Leu14=	synonymous_variant	2/4
LYRM7	NR_121658.2	n.119G>A		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYRM7	ENST00000379380.9	c.42G>A	p.Leu14=	synonymous_variant	2/5	1	NM_181705.4	P1
LYRM7	ENST00000507584.1	c.42G>A	p.Leu14=	synonymous_variant	2/4	2
LYRM7	ENST00000510516.5	c.42G>A	p.Leu14=	synonymous_variant	2/3	2
HINT1	ENST00000506207.2	n.109-8385C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0313 AC: 4764 AN: 151994 Hom.: 95 Cov.: 30

Gnomad AFR AF: 0.00820

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0207

Gnomad ASJ AF: 0.0277

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0220

Gnomad FIN AF: 0.0683

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.0456

Gnomad OTH AF: 0.0321

GnomAD3 exomes AF: 0.0338 AC: 8461 AN: 250584 Hom.: 234 AF XY: 0.0349 AC XY: 4723 AN XY: 135488

Gnomad AFR exome AF: 0.00598

Gnomad AMR exome AF: 0.0135

Gnomad ASJ exome AF: 0.0286

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0220

Gnomad FIN exome AF: 0.0759

Gnomad NFE exome AF: 0.0449

Gnomad OTH exome AF: 0.0331

GnomAD4 exome AF: 0.0391 AC: 57011 AN: 1459226 Hom.: 1341 Cov.: 28 AF XY: 0.0389 AC XY: 28227 AN XY: 726062

Gnomad4 AFR exome AF: 0.00577

Gnomad4 AMR exome AF: 0.0143

Gnomad4 ASJ exome AF: 0.0285

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0224

Gnomad4 FIN exome AF: 0.0733

Gnomad4 NFE exome AF: 0.0428

Gnomad4 OTH exome AF: 0.0328

GnomAD4 genome AF: 0.0313 AC: 4764 AN: 152112 Hom.: 95 Cov.: 30 AF XY: 0.0313 AC XY: 2330 AN XY: 74366

Gnomad4 AFR AF: 0.00817

Gnomad4 AMR AF: 0.0207

Gnomad4 ASJ AF: 0.0277

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0220

Gnomad4 FIN AF: 0.0683

Gnomad4 NFE AF: 0.0456

Gnomad4 OTH AF: 0.0318

Alfa AF: 0.0391 Hom.: 85

Bravo AF: 0.0258

Asia WGS AF: 0.0100 AC: 37 AN: 3478

EpiCase AF: 0.0425

EpiControl AF: 0.0414

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 04, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	9.4
Dann	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs113642581; hg19: chr5-130515811;