5-131180313-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_181705.4(LYRM7):c.91+146T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0468 in 466,812 control chromosomes in the GnomAD database, including 1,247 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.074 (880 hom., cov: 30)
  • Exomes 𝑓: 0.033 (367 hom.)
• Consequence: LYRM7 NM_181705.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.980

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 5-131180313-T-G is Benign according to our data. Variant chr5-131180313-T-G is described in ClinVar as [Benign]. Clinvar id is 676313.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LYRM7	NM_181705.4	c.91+146T>G		intron_variant		ENST00000379380.9
LYRM7	NM_001293735.2	c.91+146T>G		intron_variant
LYRM7	NR_121658.2	n.168+146T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LYRM7	ENST00000379380.9	c.91+146T>G		intron_variant		1	NM_181705.4	P1
LYRM7	ENST00000507584.1	c.91+146T>G		intron_variant		2
LYRM7	ENST00000510516.5	c.91+146T>G		intron_variant		2
HINT1	ENST00000506207.2	n.109-8580A>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0744 AC: 11312 AN: 152038 Hom.: 882 Cov.: 30

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0406

Gnomad ASJ AF: 0.0761

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.00773

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0300

Gnomad OTH AF: 0.0703

GnomAD4 exome AF: 0.0334 AC: 10524 AN: 314656 Hom.: 367 AF XY: 0.0331 AC XY: 5476 AN XY: 165370

Gnomad4 AFR exome AF: 0.185

Gnomad4 AMR exome AF: 0.0364

Gnomad4 ASJ exome AF: 0.0751

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0147

Gnomad4 FIN exome AF: 0.0112

Gnomad4 NFE exome AF: 0.0322

Gnomad4 OTH exome AF: 0.0490

GnomAD4 genome AF: 0.0745 AC: 11329 AN: 152156 Hom.: 880 Cov.: 30 AF XY: 0.0715 AC XY: 5319 AN XY: 74404

Gnomad4 AFR AF: 0.195

Gnomad4 AMR AF: 0.0406

Gnomad4 ASJ AF: 0.0761

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0126

Gnomad4 FIN AF: 0.00773

Gnomad4 NFE AF: 0.0301

Gnomad4 OTH AF: 0.0695

Alfa AF: 0.0194 Hom.: 17

Bravo AF: 0.0832

Asia WGS AF: 0.0160 AC: 55 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 16, 2018

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	-0.82
Cadd	Benign	8.4
Dann	Benign	0.73

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: rs60745433; hg19: chr5-130516006;