11-105026889-T-G

Variant names:

• chr11-105026889-T-G
• rs141608703
• NM_001257118.3:c.1069A>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001257118.3(CASP1):​c.1069A>C​(p.Met357Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,611,660 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: CASP1 NM_001257118.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.572
• Publications: 4 publications found

Genes affected

CASP1 (HGNC:1499): (caspase 1) This gene encodes a protein which is a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes which undergo proteolytic processing at conserved aspartic residues to produce 2 subunits, large and small, that dimerize to form the active enzyme. This gene was identified by its ability to proteolytically cleave and activate the inactive precursor of interleukin-1, a cytokine involved in the processes such as inflammation, septic shock, and wound healing. This gene has been shown to induce cell apoptosis and may function in various developmental stages. Studies of a similar gene in mouse suggest a role in the pathogenesis of Huntington disease. Alternative splicing results in transcript variants encoding distinct isoforms. [provided by RefSeq, Mar 2012]

ENSG00000303891 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01757583).
• BP6: Variant 11-105026889-T-G is Benign according to our data. Variant chr11-105026889-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2341150.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 103 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001257118.3. 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
	CASP1	NM_001257118.3	MANE Select	c.1069A>C	p.Met357Leu	missense	Exon 8 of 9	NP_001244047.1	P29466-1
	CASP1	NM_033292.4		c.1069A>C	p.Met357Leu	missense	Exon 8 of 10	NP_150634.1	P29466-1
	CASP1	NM_001223.5		c.1006A>C	p.Met336Leu	missense	Exon 7 of 9	NP_001214.1	P29466-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASP1	ENST00000533400.6	TSL:1 MANE Select	c.1069A>C	p.Met357Leu	missense	Exon 8 of 9	ENSP00000433138.1	P29466-1
	CASP1	ENST00000436863.7	TSL:1	c.1069A>C	p.Met357Leu	missense	Exon 8 of 10	ENSP00000410076.3	P29466-1
	CASP1	ENST00000526568.5	TSL:1	c.790A>C	p.Met264Leu	missense	Exon 7 of 9	ENSP00000434250.1	P29466-3

Frequencies

GnomAD3 genomes AF: 0.000684 AC: 104 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000614 AC: 154 AN: 250716 AF XY: 0.000583

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00142 AC: 2071 AN: 1459404 Hom.: 3 Cov.: 29 AF XY: 0.00130 AC XY: 946 AN XY: 726222

African (AFR) AF: 0.000299 AC: 10 AN: 33404

American (AMR) AF: 0.00 AC: 0 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86202

European-Finnish (FIN) AF: 0.0000937 AC: 5 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00174 AC: 1927 AN: 1109914

Other (OTH) AF: 0.00212 AC: 128 AN: 60320

GnomAD4 genome AF: 0.000676 AC: 103 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.000578 AC XY: 43 AN XY: 74446

African (AFR) AF: 0.000433 AC: 18 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00121 AC: 82 AN: 68000

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00116 Hom.: 1

Bravo AF: 0.000786

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000626 AC: 76

EpiCase AF: 0.00147

EpiControl AF: 0.00142

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.053
DANN	Benign	0.51
DEOGEN2	Benign	0.0098	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.31	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.48	N
PhyloP100		-0.57
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.030
Sift	Benign	0.15	T
Sift4G	Benign	0.88	T
Polyphen		0.0	B
Vest4		0.27
MutPred		0.71		Loss of phosphorylation at Y360 (P = 0.1193)
MVP		0.32
MPC		0.13
ClinPred		0.0058	T
GERP RS		-4.1
Varity_R		0.19
gMVP		0.37
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs141608703; hg19: chr11-104897616;