NM_032727.4:c.562G>C

Variant names:

• chr10-103277773-G-C
• NM_032727.4:c.562G>C
• INA p.Gly188Arg

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PS1 PM2 PP2 BP4

The NM_032727.4(INA):​c.562G>C​(p.Gly188Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: INA NM_032727.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.56
• Publications: 0 publications found

Genes affected

INA (HGNC:6057): (internexin neuronal intermediate filament protein alpha) Neurofilaments are type IV intermediate filament heteropolymers composed of light, medium, and heavy chains. Neurofilaments comprise the axoskeleton and they functionally maintain the neuronal caliber. They may also play a role in intracellular transport to axons and dendrites. This gene is a member of the intermediate filament family and is involved in the morphogenesis of neurons. [provided by RefSeq, Jun 2009]

NT5C2 (HGNC:8022): (5'-nucleotidase, cytosolic II) This gene encodes a hydrolase that serves as an important role in cellular purine metabolism by acting primarily on inosine 5'-monophosphate and other purine nucleotides. [provided by RefSeq, Oct 2011]

NT5C2 Gene-Disease associations (from GenCC):

• complex hereditary spastic paraplegia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hereditary spastic paraplegia 45

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet

ACMG classification

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

• PS1: Transcript NM_032727.4 (INA) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• 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 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.1276 (below the threshold of 3.09). Trascript score misZ: 0.35672 (below the threshold of 3.09).
• BP4: Computational evidence support a benign effect (MetaRNN=0.4232924).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032727.4. 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
	INA	NM_032727.4	MANE Select	c.562G>C	p.Gly188Arg	missense	Exon 1 of 3	NP_116116.1	Q16352

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INA	ENST00000369849.9	TSL:1 MANE Select	c.562G>C	p.Gly188Arg	missense	Exon 1 of 3	ENSP00000358865.4	Q16352
	INA	ENST00000912062.1		c.562G>C	p.Gly188Arg	missense	Exon 1 of 3	ENSP00000582121.1
	NT5C2	ENST00000676449.1		c.-644C>G		upstream_gene	N/A	ENSP00000502801.1	P49902-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Benign	0.89
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	-1.1	N
PhyloP100		1.6
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	0.86	N
REVEL	Benign	0.23
Sift	Benign	0.78	T
Sift4G	Benign	0.58	T
PromoterAI		0.014	Neutral
Varity_R		0.15
gMVP		0.63
Mutation Taster		=78/22	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr10-105037530;