chr5-131159529-T-G

Variant names:

• chr5-131159529-T-G
• rs11558046
• NM_005340.7:c.299A>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_005340.7(HINT1):​c.299A>C​(p.Glu100Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. E100G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HINT1 NM_005340.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.28
• Publications: 1 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, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_005340.7
• PM2: Very rare variant in population databases, with high coverage
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HINT1	NM_005340.7	MANE Select	c.299A>C	p.Glu100Ala	missense	Exon 3 of 3	NP_005331.1	P49773
	HINT1	NM_001437949.1		c.*2853A>C		3_prime_UTR	Exon 3 of 3	NP_001424878.1	D6RD60
	HINT1	NM_001437950.1		c.*3022A>C		3_prime_UTR	Exon 2 of 2	NP_001424879.1	D6RE99

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HINT1	ENST00000304043.10	TSL:1 MANE Select	c.299A>C	p.Glu100Ala	missense	Exon 3 of 3	ENSP00000304229.5	P49773
	HINT1	ENST00000508495.5	TSL:1	n.*251A>C		non_coding_transcript_exon	Exon 4 of 4	ENSP00000424974.1	D6REP8
	HINT1	ENST00000508495.5	TSL:1	n.*251A>C		3_prime_UTR	Exon 4 of 4	ENSP00000424974.1	D6REP8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.073
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	-0.55	N
PhyloP100		7.3
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.43
Sift	Benign	0.32	T
Sift4G	Benign	0.35	T
Polyphen		0.016	B
Vest4		0.43
MutPred		0.59		Gain of MoRF binding (P = 0.0425)
MVP		0.84
MPC		1.1
ClinPred		0.94	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.79
Mutation Taster		=47/53	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: rs11558046; hg19: chr5-130495222;