rs3748570

chr1-156670364-G-Achr1-156670364-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006617.2(NES):c.3824C>T(p.Pro1275Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 1,607,838 control chromosomes in the GnomAD database, including 345,128 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.67 (34899 hom., cov: 32)
  • Exomes 𝑓: 0.65 (310229 hom.)
• Consequence: NES NM_006617.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.24

Genes affected

NES (HGNC:7756): (nestin) This gene encodes a member of the intermediate filament protein family and is expressed primarily in nerve cells. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.881236E-7).
• BP6: Variant 1-156670364-G-A is Benign according to our data. Variant chr1-156670364-G-A is described in ClinVar as [Benign]. Clinvar id is 1238056.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.84 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NES	NM_006617.2	c.3824C>T	p.Pro1275Leu	missense_variant	4/4	ENST00000368223.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NES	ENST00000368223.4	c.3824C>T	p.Pro1275Leu	missense_variant	4/4	1	NM_006617.2	P1

Frequencies

GnomAD3 genomes AF: 0.675 AC: 102537 AN: 151902 Hom.: 34873 Cov.: 32

Gnomad AFR AF: 0.696

Gnomad AMI AF: 0.571

Gnomad AMR AF: 0.724

Gnomad ASJ AF: 0.709

Gnomad EAS AF: 0.861

Gnomad SAS AF: 0.638

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.718

Gnomad NFE AF: 0.642

Gnomad OTH AF: 0.692

GnomAD3 exomes AF: 0.677 AC: 166801 AN: 246448 Hom.: 56966 AF XY: 0.670 AC XY: 89133 AN XY: 133116

Gnomad AFR exome AF: 0.693

Gnomad AMR exome AF: 0.714

Gnomad ASJ exome AF: 0.711

Gnomad EAS exome AF: 0.865

Gnomad SAS exome AF: 0.628

Gnomad FIN exome AF: 0.663

Gnomad NFE exome AF: 0.645

Gnomad OTH exome AF: 0.680

GnomAD4 exome AF: 0.651 AC: 948281 AN: 1455820 Hom.: 310229 Cov.: 71 AF XY: 0.650 AC XY: 470479 AN XY: 723766

Gnomad4 AFR exome AF: 0.694

Gnomad4 AMR exome AF: 0.718

Gnomad4 ASJ exome AF: 0.710

Gnomad4 EAS exome AF: 0.809

Gnomad4 SAS exome AF: 0.626

Gnomad4 FIN exome AF: 0.662

Gnomad4 NFE exome AF: 0.641

Gnomad4 OTH exome AF: 0.674

GnomAD4 genome AF: 0.675 AC: 102607 AN: 152018 Hom.: 34899 Cov.: 32 AF XY: 0.678 AC XY: 50404 AN XY: 74298

Gnomad4 AFR AF: 0.695

Gnomad4 AMR AF: 0.725

Gnomad4 ASJ AF: 0.709

Gnomad4 EAS AF: 0.861

Gnomad4 SAS AF: 0.639

Gnomad4 FIN AF: 0.653

Gnomad4 NFE AF: 0.642

Gnomad4 OTH AF: 0.695

Alfa AF: 0.659 Hom.: 72421

Bravo AF: 0.683

TwinsUK AF: 0.628 AC: 2330

ALSPAC AF: 0.635 AC: 2446

ESP6500AA AF: 0.693 AC: 3055

ESP6500EA AF: 0.643 AC: 5527

ExAC AF: 0.671 AC: 81471

Asia WGS AF: 0.775 AC: 2688 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 24, 2021

This variant is associated with the following publications: (PMID: 18724036) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	12
Dann	Benign	0.65
DEOGEN2	Benign	0.094	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	5.9e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	3.3	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.054
MPC		0.057
ClinPred		0.0052	T
GERP RS		5.0
Varity_R		0.040
gMVP		0.017

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

Other links and lift over

dbSNP: rs3748570; hg19: chr1-156640156;