NM_181705.4:c.19-151A>T

Variant names:

• chr5-131179944-A-T
• rs183113457
• NM_181705.4:c.19-151A>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_181705.4(LYRM7):​c.19-151A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00911 in 453,152 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0089 (17 hom., cov: 30)
  • Exomes 𝑓: 0.0092 (9 hom.)
• Consequence: LYRM7 NM_181705.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.51
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 5-131179944-A-T is Benign according to our data. Variant chr5-131179944-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1209485.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00887 (1330/149926) while in subpopulation NFE AF = 0.0127 (853/67308). AF 95% confidence interval is 0.012. There are 17 homozygotes in GnomAd4. There are 681 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

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.19-151A>T		intron	N/A	NP_859056.2	Q5U5X0
	LYRM7	NM_001293735.2		c.19-151A>T		intron	N/A	NP_001280664.1	D6RBV5
	LYRM7	NR_121658.2		n.96-151A>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LYRM7	ENST00000379380.9	TSL:1 MANE Select	c.19-151A>T		intron	N/A	ENSP00000368688.4	Q5U5X0
	LYRM7	ENST00000855899.1		c.19-151A>T		intron	N/A	ENSP00000525958.1
	LYRM7	ENST00000931593.1		c.13-151A>T		intron	N/A	ENSP00000601652.1

Frequencies

GnomAD3 genomes AF: 0.00888 AC: 1330 AN: 149816 Hom.: 17 Cov.: 30

Gnomad AFR AF: 0.00250

Gnomad AMI AF: 0.0476

Gnomad AMR AF: 0.00599

Gnomad ASJ AF: 0.00786

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.00234

Gnomad FIN AF: 0.0176

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.0102

GnomAD4 exome AF: 0.00922 AC: 2797 AN: 303226 Hom.: 9 AF XY: 0.00881 AC XY: 1440 AN XY: 163464

African (AFR) AF: 0.00382 AC: 26 AN: 6806

American (AMR) AF: 0.00623 AC: 67 AN: 10750

Ashkenazi Jewish (ASJ) AF: 0.0100 AC: 90 AN: 8956

East Asian (EAS) AF: 0.000320 AC: 6 AN: 18746

South Asian (SAS) AF: 0.00213 AC: 67 AN: 31522

European-Finnish (FIN) AF: 0.0117 AC: 255 AN: 21804

Middle Eastern (MID) AF: 0.00388 AC: 9 AN: 2318

European-Non Finnish (NFE) AF: 0.0116 AC: 2138 AN: 184994

Other (OTH) AF: 0.00802 AC: 139 AN: 17330

GnomAD4 genome AF: 0.00887 AC: 1330 AN: 149926 Hom.: 17 Cov.: 30 AF XY: 0.00932 AC XY: 681 AN XY: 73098

African (AFR) AF: 0.00250 AC: 102 AN: 40870

American (AMR) AF: 0.00599 AC: 90 AN: 15036

Ashkenazi Jewish (ASJ) AF: 0.00786 AC: 27 AN: 3434

East Asian (EAS) AF: 0.000390 AC: 2 AN: 5126

South Asian (SAS) AF: 0.00234 AC: 11 AN: 4692

European-Finnish (FIN) AF: 0.0176 AC: 179 AN: 10196

Middle Eastern (MID) AF: 0.00690 AC: 2 AN: 290

European-Non Finnish (NFE) AF: 0.0127 AC: 853 AN: 67308

Other (OTH) AF: 0.0101 AC: 21 AN: 2070

Alfa AF: 0.0104 Hom.: 0

Bravo AF: 0.00764

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.27
DANN	Benign	0.49
PhyloP100		-3.5
Mutation Taster		=100/0	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: rs183113457; hg19: chr5-130515637;