chr10-103277977-G-T

Variant names:

• chr10-103277977-G-T
• NM_032727.4:c.766G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_032727.4(INA):​c.766G>T​(p.Val256Leu) 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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: INA NM_032727.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.17
• 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 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).
• BP4: Computational evidence support a benign effect (MetaRNN=0.3004849).

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.766G>T	p.Val256Leu	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.766G>T	p.Val256Leu	missense	Exon 1 of 3	ENSP00000358865.4	Q16352
	INA	ENST00000912062.1		c.766G>T	p.Val256Leu	missense	Exon 1 of 3	ENSP00000582121.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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	Benign	0.20
BayesDel_addAF	Benign	-0.0061	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.095
Eigen_PC	Benign	0.054
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.26
Sift	Benign	0.099	T
Sift4G	Benign	0.21	T
Polyphen		0.63	P
Vest4		0.20
MutPred		0.50		Loss of methylation at K258 (P = 0.1414)
MVP		0.95
MPC		1.0
ClinPred		0.68	D
GERP RS		4.3
PromoterAI		-0.0025	Neutral
Varity_R		0.10
gMVP		0.76
Mutation Taster		=64/36	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

Other links and lift over

hg19: chr10-105037734;