1-156669792-T-C

Variant names:

• chr1-156669792-T-C
• rs74118730
• NM_006617.2:c.4396A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006617.2(NES):​c.4396A>G​(p.Ser1466Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 1,613,966 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1466R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (37 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (35 hom.)
• Consequence: NES NM_006617.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.715
• Publications: 1 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=0.0026652515).
• BP6: Variant 1-156669792-T-C is Benign according to our data. Variant chr1-156669792-T-C is described in ClinVar as Benign. ClinVar VariationId is 782391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0118 (1788/152144) while in subpopulation AFR AF = 0.0414 (1716/41496). AF 95% confidence interval is 0.0397. There are 37 homozygotes in GnomAd4. There are 867 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 37 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006617.2. 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
	NES	NM_006617.2	MANE Select	c.4396A>G	p.Ser1466Gly	missense	Exon 4 of 4	NP_006608.1	P48681

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NES	ENST00000368223.4	TSL:1 MANE Select	c.4396A>G	p.Ser1466Gly	missense	Exon 4 of 4	ENSP00000357206.3	P48681
	NES	ENST00000867897.1		c.3430A>G	p.Ser1144Gly	missense	Exon 4 of 4	ENSP00000537956.1

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1782 AN: 152026 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0414

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00329 AC: 826 AN: 251118 AF XY: 0.00231

Gnomad AFR exome AF: 0.0448

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00125 AC: 1825 AN: 1461822 Hom.: 35 Cov.: 32 AF XY: 0.00105 AC XY: 760 AN XY: 727224

African (AFR) AF: 0.0430 AC: 1439 AN: 33480

American (AMR) AF: 0.00295 AC: 132 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0000477 AC: 53 AN: 1111998

Other (OTH) AF: 0.00300 AC: 181 AN: 60394

GnomAD4 genome AF: 0.0118 AC: 1788 AN: 152144 Hom.: 37 Cov.: 32 AF XY: 0.0117 AC XY: 867 AN XY: 74384

African (AFR) AF: 0.0414 AC: 1716 AN: 41496

American (AMR) AF: 0.00333 AC: 51 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67980

Other (OTH) AF: 0.00711 AC: 15 AN: 2110

Alfa AF: 0.00399 Hom.: 10

Bravo AF: 0.0135

ESP6500AA AF: 0.0377 AC: 166

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00403 AC: 489

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	10
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.71
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.10
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.17	T
Polyphen		0.041	B
Vest4		0.23
MVP		0.66
MPC		0.090
ClinPred		0.016	T
GERP RS		0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.016
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs74118730; hg19: chr1-156639584;