chr10-103277603-A-T

Variant names:

• chr10-103277603-A-T
• rs776591839
• NM_032727.4:c.392A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_032727.4(INA):​c.392A>T​(p.Gln131Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000718 in 1,393,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. Q131R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: INA NM_032727.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.00
• 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: Uncertain_significance. The variant received 4 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, 0.813

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.392A>T	p.Gln131Leu	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.392A>T	p.Gln131Leu	missense	Exon 1 of 3	ENSP00000358865.4	Q16352
	INA	ENST00000912062.1		c.392A>T	p.Gln131Leu	missense	Exon 1 of 3	ENSP00000582121.1
	NT5C2	ENST00000676449.1		c.-474T>A		5_prime_UTR	Exon 1 of 18	ENSP00000502801.1	P49902-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000602 AC: 1 AN: 166054 AF XY: 0.0000107

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.18e-7 AC: 1 AN: 1393702 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 691996

African (AFR) AF: 0.00 AC: 0 AN: 29198

American (AMR) AF: 0.00 AC: 0 AN: 37296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24548

East Asian (EAS) AF: 0.00 AC: 0 AN: 34658

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39064

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4992

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085514

Other (OTH) AF: 0.00 AC: 0 AN: 57816

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000846 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.73
Sift	Benign	0.057	T
Sift4G	Benign	0.063	T
Polyphen		1.0	D
Vest4		0.55
MutPred		0.43		Loss of disorder (P = 0.0873)
MVP		0.95
MPC		2.1
ClinPred		0.96	D
GERP RS		4.0
PromoterAI		0.12	Neutral
Varity_R		0.72
gMVP		0.38
Mutation Taster		=37/63	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: rs776591839; hg19: chr10-105037360;