NM_032727.4:c.315C>A

Variant names:

• chr10-103277526-C-A
• NM_032727.4:c.315C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_032727.4(INA):​c.315C>A​(p.Phe105Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,434,178 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: INA NM_032727.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07
• 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 7 ACMG points.

• 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).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942

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.315C>A	p.Phe105Leu	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.315C>A	p.Phe105Leu	missense	Exon 1 of 3	ENSP00000358865.4	Q16352
	INA	ENST00000912062.1		c.315C>A	p.Phe105Leu	missense	Exon 1 of 3	ENSP00000582121.1
	NT5C2	ENST00000676449.1		c.-397G>T		5_prime_UTR	Exon 1 of 18	ENSP00000502801.1	P49902-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1434178 Hom.: 0 Cov.: 33 AF XY: 0.00000140 AC XY: 1 AN XY: 713536

African (AFR) AF: 0.00 AC: 0 AN: 30662

American (AMR) AF: 0.00 AC: 0 AN: 42362

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25458

East Asian (EAS) AF: 0.00 AC: 0 AN: 37220

South Asian (SAS) AF: 0.00 AC: 0 AN: 83374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1102166

Other (OTH) AF: 0.00 AC: 0 AN: 59454

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.4	L
PhyloP100		1.1
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.017	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.63		Gain of disorder (P = 0.1674)
MVP		0.98
MPC		2.3
ClinPred		0.95	D
GERP RS		3.1
PromoterAI		-0.016	Neutral
Varity_R		0.72
gMVP		0.72
Mutation Taster		=38/62	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

hg19: chr10-105037283;