NM_006617.2:c.3824C>T

Variant names:

• chr1-156670364-G-A
• rs3748570
• NM_006617.2:c.3824C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.24
• Publications: 41 publications found

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

Our verdict: Benign. The variant received -20 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 VariationId is 1238056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
NES	NM_006617.2	c.3824C>T	p.Pro1275Leu	missense_variant	Exon 4 of 4	ENST00000368223.4	NP_006608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NES	ENST00000368223.4	c.3824C>T	p.Pro1275Leu	missense_variant	Exon 4 of 4	1	NM_006617.2	ENSP00000357206.3

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

GnomAD2 exomes AF: 0.677 AC: 166801 AN: 246448 AF XY: 0.670

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 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

African (AFR) AF: 0.694 AC: 23134 AN: 33318

American (AMR) AF: 0.718 AC: 31601 AN: 44016

Ashkenazi Jewish (ASJ) AF: 0.710 AC: 18149 AN: 25572

East Asian (EAS) AF: 0.809 AC: 32080 AN: 39646

South Asian (SAS) AF: 0.626 AC: 53471 AN: 85354

European-Finnish (FIN) AF: 0.662 AC: 35198 AN: 53138

Middle Eastern (MID) AF: 0.625 AC: 3589 AN: 5742

European-Non Finnish (NFE) AF: 0.641 AC: 710539 AN: 1108954

Other (OTH) AF: 0.674 AC: 40520 AN: 60080

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

African (AFR) AF: 0.695 AC: 28825 AN: 41460

American (AMR) AF: 0.725 AC: 11065 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.709 AC: 2461 AN: 3472

East Asian (EAS) AF: 0.861 AC: 4429 AN: 5144

South Asian (SAS) AF: 0.639 AC: 3081 AN: 4822

European-Finnish (FIN) AF: 0.653 AC: 6923 AN: 10600

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.642 AC: 43623 AN: 67930

Other (OTH) AF: 0.695 AC: 1467 AN: 2112

Alfa AF: 0.659 Hom.: 146233

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 24, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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
PhyloP100		1.2
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
Mutation Taster		=100/0	polymorphism (auto)

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: rs3748570; hg19: chr1-156640156; COSMIC: COSV100957909;