6-109000602-G-T

Position:

• chr6-109000602-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014454.3(SESN1):​c.618C>A​(p.Asp206Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SESN1 NM_014454.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48

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]

SESN1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.781

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SESN1	NM_014454.3	c.618C>A	p.Asp206Glu	missense_variant	4/10	ENST00000436639.7	NP_055269.1
SESN1	NM_001199933.2	c.441C>A	p.Asp147Glu	missense_variant	4/10		NP_001186862.1
SESN1	NM_001199934.2	c.243C>A	p.Asp81Glu	missense_variant	4/10		NP_001186863.1
ARMC2	XM_047419396.1	c.2446+35462G>T		intron_variant			XP_047275352.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SESN1	ENST00000436639.7	c.618C>A	p.Asp206Glu	missense_variant	4/10	1	NM_014454.3	ENSP00000393762.2
SESN1	ENST00000356644.7	c.441C>A	p.Asp147Glu	missense_variant	4/10	1		ENSP00000349061.7
SESN1	ENST00000302071.6	c.243C>A	p.Asp81Glu	missense_variant	4/10	1		ENSP00000306734.2
SESN1	ENST00000523632.1	n.257C>A		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2023

The c.618C>A (p.D206E) alteration is located in exon 4 (coding exon 4) of the SESN1 gene. This alteration results from a C to A substitution at nucleotide position 618, causing the aspartic acid (D) at amino acid position 206 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;.;T
Eigen	Benign	0.036
Eigen_PC	Benign	0.031
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	.;.;M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Benign	0.26
Sift	Benign	0.056	T;T;D
Sift4G	Benign	0.083	T;T;T
Polyphen		0.95	P;.;D
Vest4		0.76
MutPred		0.62		.;.;Gain of ubiquitination at K149 (P = 0.0716);
MVP		0.78
MPC		0.76
ClinPred		0.97	D
GERP RS		2.3
Varity_R		0.29
gMVP		0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-109321805;