rs587777433

Variant names:

• chr5-131180149-G-A
• rs587777433
• NM_181705.4:c.73G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_181705.4(LYRM7):​c.73G>A​(p.Asp25Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,190 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LYRM7 NM_181705.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.71
• Publications: 8 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767
• PP5: Variant 5-131180149-G-A is Pathogenic according to our data. Variant chr5-131180149-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 135664.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LYRM7	NM_181705.4	c.73G>A	p.Asp25Asn	missense_variant	Exon 2 of 5	ENST00000379380.9	NP_859056.2
LYRM7	NM_001293735.2	c.73G>A	p.Asp25Asn	missense_variant	Exon 2 of 4		NP_001280664.1
LYRM7	NR_121658.2	n.150G>A		non_coding_transcript_exon_variant	Exon 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LYRM7	ENST00000379380.9	c.73G>A	p.Asp25Asn	missense_variant	Exon 2 of 5	1	NM_181705.4	ENSP00000368688.4
LYRM7	ENST00000507584.1	c.73G>A	p.Asp25Asn	missense_variant	Exon 2 of 4	2		ENSP00000423991.1
LYRM7	ENST00000510516.5	c.73G>A	p.Asp25Asn	missense_variant	Exon 2 of 3	2		ENSP00000423283.1
HINT1	ENST00000506207.2	n.109-8416C>T		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459190 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 726096

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.00 AC: 0 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109760

Other (OTH) AF: 0.0000166 AC: 1 AN: 60290

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Mitochondrial complex III deficiency nuclear type 8 Pathogenic:1

Dec 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Pathogenic	3.2	M;.;.
PhyloP100		3.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.025	D;T;D
Polyphen		1.0	D;.;.
Vest4		0.74
MutPred		0.44		Gain of MoRF binding (P = 0.0489);Gain of MoRF binding (P = 0.0489);Gain of MoRF binding (P = 0.0489);
MVP		0.62
MPC		0.29
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.81
gMVP		0.83
Mutation Taster		=31/69	disease causing (ClinVar)

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: rs587777433; hg19: chr5-130515842;