6-109002316-G-T

Position:

• chr6-109002316-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.77

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]

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
SESN1	NM_014454.3	c.307C>A	p.Leu103Ile	missense_variant	2/10	ENST00000436639.7	NP_055269.1
SESN1	NM_001199933.2	c.130C>A	p.Leu44Ile	missense_variant	2/10		NP_001186862.1
SESN1	NM_001199934.2	c.-69C>A		5_prime_UTR_variant	2/10		NP_001186863.1
ARMC2	XM_047419396.1	c.2446+37176G>T		intron_variant			XP_047275352.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SESN1	ENST00000436639.7	c.307C>A	p.Leu103Ile	missense_variant	2/10	1	NM_014454.3	ENSP00000393762.2
SESN1	ENST00000356644.7	c.130C>A	p.Leu44Ile	missense_variant	2/10	1		ENSP00000349061.7
SESN1	ENST00000302071.6	c.-69C>A		5_prime_UTR_variant	2/10	1		ENSP00000306734.2

Frequencies

GnomAD3 genomes AF: 0.0901 AC: 13698 AN: 152016 Hom.: 838 Cov.: 32

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

GnomAD3 exomes AF: 0.110 AC: 27636 AN: 251206 Hom.: 1896 AF XY: 0.118 AC XY: 16026 AN XY: 135764

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 SAS exome AF: 0.187

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.: 30 AF XY: 0.122 AC XY: 88297 AN XY: 726116

Gnomad4 AFR exome AF: 0.0193

Gnomad4 AMR exome AF: 0.0591

Gnomad4 ASJ exome AF: 0.0996

Gnomad4 EAS exome AF: 0.0548

Gnomad4 SAS exome AF: 0.189

Gnomad4 FIN exome AF: 0.149

Gnomad4 NFE exome AF: 0.120

Gnomad4 OTH exome AF: 0.113

GnomAD4 genome AF: 0.0900 AC: 13694 AN: 152134 Hom.: 838 Cov.: 32 AF XY: 0.0910 AC XY: 6766 AN XY: 74350

Gnomad4 AFR AF: 0.0212

Gnomad4 AMR AF: 0.0714

Gnomad4 ASJ AF: 0.0989

Gnomad4 EAS AF: 0.0465

Gnomad4 SAS AF: 0.187

Gnomad4 FIN AF: 0.152

Gnomad4 NFE AF: 0.122

Gnomad4 OTH AF: 0.102

Alfa AF: 0.114 Hom.: 2767

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	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.044	.;T
Eigen	Benign	0.016
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;D
MetaRNN	Benign	0.0013	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	.;N
PrimateAI	Uncertain	0.51	T
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	T
GERP RS		5.6
Varity_R		0.12
gMVP		0.37

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: rs2273668; hg19: chr6-109323519; COSMIC: COSV57420512; COSMIC: COSV57420512;