5-131171025-G-C

Variant names:

• chr5-131171025-G-C
• rs755037848
• NM_181705.4:c.5G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181705.4(LYRM7):​c.5G>C​(p.Gly2Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000072 in 1,388,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. G2E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: LYRM7 NM_181705.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46
• Publications: 0 publications found

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]

HINT1 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Gamstorp-Wohlfart syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08465147).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181705.4. 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
	LYRM7	NM_181705.4	MANE Select	c.5G>C	p.Gly2Ala	missense	Exon 1 of 5	NP_859056.2	Q5U5X0
	LYRM7	NM_001293735.2		c.5G>C	p.Gly2Ala	missense	Exon 1 of 4	NP_001280664.1	D6RBV5
	LYRM7	NR_121658.2		n.82G>C		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYRM7	ENST00000379380.9	TSL:1 MANE Select	c.5G>C	p.Gly2Ala	missense	Exon 1 of 5	ENSP00000368688.4	Q5U5X0
	LYRM7	ENST00000855899.1		c.5G>C	p.Gly2Ala	missense	Exon 1 of 5	ENSP00000525958.1
	LYRM7	ENST00000931593.1		c.5G>C	p.Gly2Ala	missense	Exon 1 of 5	ENSP00000601652.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.20e-7 AC: 1 AN: 1388238 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 688788

African (AFR) AF: 0.00 AC: 0 AN: 28490

American (AMR) AF: 0.00 AC: 0 AN: 28840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23706

East Asian (EAS) AF: 0.00 AC: 0 AN: 33488

South Asian (SAS) AF: 0.00 AC: 0 AN: 74986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5544

European-Non Finnish (NFE) AF: 9.23e-7 AC: 1 AN: 1083846

Other (OTH) AF: 0.00 AC: 0 AN: 57312

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.56
DEOGEN2	Benign	0.0023	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.5
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.32	N
REVEL	Benign	0.083
Sift	Benign	0.43	T
Sift4G	Benign	0.88	T
Polyphen		0.0010	B
Vest4		0.074
MutPred		0.21		Loss of methylation at R3 (P = 0.0901)
MVP		0.072
MPC		0.042
ClinPred		0.19	T
GERP RS		3.9
PromoterAI		0.081	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.042
gMVP		0.22
Mutation Taster		=83/17	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: rs755037848; hg19: chr5-130506718;