6-109002316-G-T

Variant names:

• chr6-109002316-G-T
• rs2273668
• NM_014454.3:c.307C>A

Variant summary

Our verdict is Benign. The variant received -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. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.77
• Publications: 41 publications found

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]

ARMC2 Gene-Disease associations (from GenCC):

• spermatogenic failure 38

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014454.3. 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
	SESN1	NM_014454.3	MANE Select	c.307C>A	p.Leu103Ile	missense	Exon 2 of 10	NP_055269.1	Q9Y6P5-2
	SESN1	NM_001199933.2		c.130C>A	p.Leu44Ile	missense	Exon 2 of 10	NP_001186862.1	Q9Y6P5-1
	SESN1	NM_001199934.2		c.-69C>A		5_prime_UTR	Exon 2 of 10	NP_001186863.1	Q9Y6P5-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SESN1	ENST00000436639.7	TSL:1 MANE Select	c.307C>A	p.Leu103Ile	missense	Exon 2 of 10	ENSP00000393762.2	Q9Y6P5-2
	SESN1	ENST00000356644.7	TSL:1	c.130C>A	p.Leu44Ile	missense	Exon 2 of 10	ENSP00000349061.7	Q9Y6P5-1
	SESN1	ENST00000302071.6	TSL:1	c.-69C>A		5_prime_UTR	Exon 2 of 10	ENSP00000306734.2	Q9Y6P5-3

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

GnomAD2 exomes AF: 0.110 AC: 27636 AN: 251206 AF XY: 0.118

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

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

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

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: 57 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8325 AN: 67992

Other (OTH) AF: 0.102 AC: 216 AN: 2116

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 v4.9

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
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.8
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.080
Sift	Benign	0.11	T
Sift4G	Benign	0.16	T
Polyphen		0.50	P
Vest4		0.15
MPC		0.61
ClinPred		0.012	T
GERP RS		5.6
Varity_R		0.12
gMVP		0.37
Mutation Taster		=279/21	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: rs2273668; hg19: chr6-109323519; COSMIC: COSV57420512; COSMIC: COSV57420512;