6-109002316-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_014454.3(SESN1):c.307C>A(p.Leu103Ile) variant causes a missense change. The variant allele was found at a frequency of 0.116 in 1,611,464 control chromosomes in the GnomAD database, including 11,940 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.090 ( 838 hom., cov: 32)

Exomes 𝑓: 0.12 ( 11102 hom. )

Consequence

SESN1
NM_014454.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.77

Publications

41 publications found

Variant links:

Genes affected

SESN1 (HGNC:21595): (sestrin 1) This gene encodes a member of the sestrin family. Sestrins are induced by the p53 tumor suppressor protein and play a role in the cellular response to DNA damage and oxidative stress. The encoded protein mediates p53 inhibition of cell growth by activating AMP-activated protein kinase, which results in the inhibition of the mammalian target of rapamycin protein. The encoded protein also plays a critical role in antioxidant defense by regenerating overoxidized peroxiredoxins, and the expression of this gene is a potential marker for exposure to radiation. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

SESN1 links:

ARMC2 (HGNC:23045): (armadillo repeat containing 2) Involved in sperm axoneme assembly. Implicated in spermatogenic failure 38. [provided by Alliance of Genome Resources, Apr 2022]

ARMC2 Gene-Disease associations (from GenCC):

spermatogenic failure 38
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
non-syndromic male infertility due to sperm motility disorder
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ARMC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0012729466).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SESN1	NM_014454.3 link	c.307C>A	p.Leu103Ile	missense_variant	Exon 2 of 10	ENST00000436639.7	NP_055269.1	Q9Y6P5-2
SESN1	NM_001199933.2 link	c.130C>A	p.Leu44Ile	missense_variant	Exon 2 of 10		NP_001186862.1	Q9Y6P5-1
SESN1	NM_001199934.2 link	c.-69C>A		5_prime_UTR_variant	Exon 2 of 10		NP_001186863.1	Q9Y6P5-3
ARMC2	XM_047419396.1 link	c.2446+37176G>T		intron_variant	Intron 17 of 17		XP_047275352.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SESN1	ENST00000436639.7 link	c.307C>A	p.Leu103Ile	missense_variant	Exon 2 of 10	1	NM_014454.3	ENSP00000393762.2	Q9Y6P5-2
SESN1	ENST00000356644.7 link	c.130C>A	p.Leu44Ile	missense_variant	Exon 2 of 10	1		ENSP00000349061.7	Q9Y6P5-1
SESN1	ENST00000302071.6 link	c.-69C>A		5_prime_UTR_variant	Exon 2 of 10	1		ENSP00000306734.2	Q9Y6P5-3

Frequencies

GnomAD3 genomes

AF:

0.0901

AC:

13698

AN:

152016

Hom.:

838

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0213

Gnomad AMI

AF:

0.0395

Gnomad AMR

AF:

0.0715

Gnomad ASJ

AF:

0.0989

Gnomad EAS

AF:

0.0462

Gnomad SAS

AF:

0.187

Gnomad FIN

AF:

0.152

Gnomad MID

AF:

0.193

Gnomad NFE

AF:

0.122

Gnomad OTH

AF:

0.104

GnomAD2 exomes

AF:

0.110

AC:

27636

AN:

251206

AF XY:

0.118

show subpopulations

Gnomad AFR exome

AF:

0.0185

Gnomad AMR exome

AF:

0.0582

Gnomad ASJ exome

AF:

0.0971

Gnomad EAS exome

AF:

0.0522

Gnomad FIN exome

AF:

0.148

Gnomad NFE exome

AF:

0.121

Gnomad OTH exome

AF:

0.119

GnomAD4 exome

AF:

0.119

AC:

173026

AN:

1459330

Hom.:

11102

Cov.:

AF XY:

0.122

AC XY:

88297

AN XY:

726116

show subpopulations

African (AFR)

AF:

0.0193

AC:

645

AN:

33452

American (AMR)

AF:

0.0591

AC:

2640

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.0996

AC:

2601

AN:

26102

East Asian (EAS)

AF:

0.0548

AC:

2173

AN:

39664

South Asian (SAS)

AF:

0.189

AC:

16319

AN:

86132

European-Finnish (FIN)

AF:

0.149

AC:

7931

AN:

53362

Middle Eastern (MID)

AF:

0.171

AC:

987

AN:

5758

European-Non Finnish (NFE)

AF:

0.120

AC:

132934

AN:

1109854

Other (OTH)

AF:

0.113

AC:

6796

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

7220

14440

21661

28881

36101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4800

9600

14400

19200

24000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0900

AC:

13694

AN:

152134

Hom.:

838

Cov.:

AF XY:

0.0910

AC XY:

6766

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.0212

AC:

882

AN:

41540

American (AMR)

AF:

0.0714

AC:

1090

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0989

AC:

343

AN:

3468

East Asian (EAS)

AF:

0.0465

AC:

241

AN:

5178

South Asian (SAS)

AF:

0.187

AC:

901

AN:

4822

European-Finnish (FIN)

AF:

0.152

AC:

1603

AN:

10542

Middle Eastern (MID)

AF:

0.194

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.122

AC:

8325

AN:

67992

Other (OTH)

AF:

0.102

AC:

216

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

622

1243

1865

2486

3108

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

170

340

510

680

850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.110

Hom.:

3926

Bravo

AF:

0.0786

TwinsUK

AF:

0.133

AC:

494

ALSPAC

AF:

0.118

AC:

453

ESP6500AA

AF:

0.0241

AC:

106

ESP6500EA

AF:

0.117

AC:

1004

ExAC

AF:

0.112

AC:

13591

Asia WGS

AF:

0.0900

AC:

317

AN:

3478

EpiCase

AF:

0.125

EpiControl

AF:

0.128

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.044

.;T

Eigen

Benign

0.016

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.89

D;D

MetaRNN

Benign

0.0013

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

.;N

PhyloP100

3.8

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.29

N;N

REVEL

Benign

0.080

Sift

Benign

0.11

T;T

Sift4G

Benign

0.16

T;T

Polyphen

0.50

P;B

Vest4

0.15

MPC

0.61

ClinPred

0.012

GERP RS

5.6

Varity_R

0.12

gMVP

0.37

Mutation Taster

=279/21

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over