5-131171038-G-A

Variant names:

• chr5-131171038-G-A
• rs1347420866
• NM_181705.4:c.18G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_181705.4(LYRM7):​c.18G>A​(p.Lys6Lys) variant causes a splice region, synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LYRM7 NM_181705.4 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.63
• 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, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.18G>A	p.Lys6Lys	splice_region synonymous	Exon 1 of 5	NP_859056.2	Q5U5X0
	LYRM7	NM_001293735.2		c.18G>A	p.Lys6Lys	splice_region synonymous	Exon 1 of 4	NP_001280664.1	D6RBV5
	LYRM7	NR_121658.2		n.95G>A		splice_region 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.18G>A	p.Lys6Lys	splice_region synonymous	Exon 1 of 5	ENSP00000368688.4	Q5U5X0
	LYRM7	ENST00000855899.1		c.18G>A	p.Lys6Lys	splice_region synonymous	Exon 1 of 5	ENSP00000525958.1
	LYRM7	ENST00000931592.1		c.18G>A	p.Lys6Lys	splice_region synonymous	Exon 1 of 5	ENSP00000601651.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 165576 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1379548 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 684326

African (AFR) AF: 0.00 AC: 0 AN: 27884

American (AMR) AF: 0.00 AC: 0 AN: 26070

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23266

East Asian (EAS) AF: 0.00 AC: 0 AN: 33110

South Asian (SAS) AF: 0.00 AC: 0 AN: 73286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52032

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081418

Other (OTH) AF: 0.00 AC: 0 AN: 56964

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Benign	0.89
PhyloP100		3.6
PromoterAI		-0.41	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.27		Position offset: -42
DS_DL_spliceai		0.89		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1347420866; hg19: chr5-130506731;