Genetic Variant NM_032727.4:c.562G>A (chr10-103277773-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP4

The NM_032727.4(INA):c.562G>A(p.Gly188Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000041 in 1,487,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

INA
NM_032727.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.56

Variant links:

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]

INA links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-103277773-G-A is Pathogenic according to our data. Variant chr10-103277773-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402160.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-103277773-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.41955626). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INA	NM_032727.4 link	c.562G>A	p.Gly188Arg	missense_variant	Exon 1 of 3	ENST00000369849.9	NP_116116.1	Q16352

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INA	ENST00000369849.9 link	c.562G>A	p.Gly188Arg	missense_variant	Exon 1 of 3	1	NM_032727.4	ENSP00000358865.4		Q16352
NT5C2	ENST00000676449.1 link	c.-644C>T		upstream_gene_variant				ENSP00000502801.1		P49902-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000348

AC:

AN:

86318

Hom.:

AF XY:

0.0000418

AC XY:

AN XY:

47874

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000588

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000599

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000434

AC:

AN:

1335002

Hom.:

Cov.:

AF XY:

0.0000442

AC XY:

AN XY:

656498

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000356

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000141

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000434

Gnomad4 OTH exome

AF:

0.000144

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152026

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74242

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000436

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Abnormal brain morphology

Pathogenic:1

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.28

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.19

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.89

MetaRNN

Benign

0.42

MetaSVM

Benign

-0.44

MutationAssessor

Benign

-1.1

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

0.86

REVEL

Benign

0.21

Sift

Benign

0.78

Sift4G

Benign

0.58

Polyphen

0.21

Vest4

0.15

MutPred

0.40

Gain of MoRF binding (P = 0.0338);

MVP

0.96

MPC

1.2

ClinPred

0.78

GERP RS

3.1

Varity_R

0.15

gMVP

0.63

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over