5-131159562-C-T

Variant names:

• chr5-131159562-C-T
• rs397514490
• NM_005340.7:c.266G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_005340.7(HINT1):​c.266G>A​(p.Gly89Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,432 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G89V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HINT1 NM_005340.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.49
• Publications: 0 publications found

Genes affected

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 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_005340.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-131159562-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 37314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 10 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.44207 (below the threshold of 3.09). Trascript score misZ: 0.49961 (below the threshold of 3.09). GenCC associations: The gene is linked to Gamstorp-Wohlfart syndrome, Charcot-Marie-Tooth disease.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005340.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HINT1	NM_005340.7	MANE Select	c.266G>A	p.Gly89Asp	missense	Exon 3 of 3	NP_005331.1
	HINT1	NR_024610.3		n.506G>A		non_coding_transcript_exon	Exon 4 of 4
	HINT1	NR_024611.3		n.352G>A		non_coding_transcript_exon	Exon 3 of 3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HINT1	ENST00000304043.10	TSL:1 MANE Select	c.266G>A	p.Gly89Asp	missense	Exon 3 of 3	ENSP00000304229.5
	HINT1	ENST00000508495.5	TSL:1	n.*218G>A		non_coding_transcript_exon	Exon 4 of 4	ENSP00000424974.1
	HINT1	ENST00000508495.5	TSL:1	n.*218G>A		3_prime_UTR	Exon 4 of 4	ENSP00000424974.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461432 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727032

⚠️ 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: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111696

Other (OTH) AF: 0.00 AC: 0 AN: 60374

⚠️ 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.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.019	D
Polyphen		0.25	B
Vest4		0.44
MutPred		0.81		Gain of solvent accessibility (P = 0.0648)
MVP		0.90
MPC		1.2
ClinPred		0.97	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.80
Mutation Taster		=16/84	disease causing

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: rs397514490; hg19: chr5-130495255;