5-115832606-T-A

Variant names:

• chr5-115832606-T-A
• rs370194003
• NM_004707.4:c.359A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004707.4(ATG12):​c.359A>T​(p.Tyr120Phe) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y120S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0000012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATG12 NM_004707.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.14
• Publications: 0 publications found

Genes affected

ATG12 (HGNC:588): (autophagy related 12) Autophagy is a process of bulk protein degradation in which cytoplasmic components, including organelles, are enclosed in double-membrane structures called autophagosomes and delivered to lysosomes or vacuoles for degradation. ATG12 is the human homolog of a yeast protein involved in autophagy (Mizushima et al., 1998 [PubMed 9852036]).[supplied by OMIM, Mar 2008]

ATG12 Gene-Disease associations (from GenCC):

• colorectal cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

LOC124901049 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24768975).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004707.4. 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
	ATG12	NM_004707.4	MANE Select	c.359A>T	p.Tyr120Phe	missense	Exon 3 of 4	NP_004698.3
	ATG12	NM_001277783.2		c.222A>T	p.Leu74Leu	synonymous	Exon 2 of 3	NP_001264712.1	O94817-4
	ATG12	NR_033362.2		n.489A>T		non_coding_transcript_exon	Exon 4 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATG12	ENST00000509910.2	TSL:1 MANE Select	c.359A>T	p.Tyr120Phe	missense	Exon 3 of 4	ENSP00000425107.1	O94817-1
	ATG12	ENST00000500945.2	TSL:1	c.222A>T	p.Leu74Leu	synonymous	Exon 2 of 3	ENSP00000425164.1	O94817-4
	ATG12	ENST00000505252.1	TSL:1	n.1747A>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 125188 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000124 AC: 1 AN: 805878 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 415726

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 16056

American (AMR) AF: 0.00 AC: 0 AN: 22636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17474

East Asian (EAS) AF: 0.00 AC: 0 AN: 28090

South Asian (SAS) AF: 0.00 AC: 0 AN: 58850

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3124

European-Non Finnish (NFE) AF: 0.00000173 AC: 1 AN: 578396

Other (OTH) AF: 0.00 AC: 0 AN: 35634

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 125188 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 58816

African (AFR) AF: 0.00 AC: 0 AN: 32614

American (AMR) AF: 0.00 AC: 0 AN: 10330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3276

East Asian (EAS) AF: 0.00 AC: 0 AN: 4174

South Asian (SAS) AF: 0.00 AC: 0 AN: 3884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5502

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 234

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 62646

Other (OTH) AF: 0.00 AC: 0 AN: 1670

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.093	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.036
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.91	T
PhyloP100		5.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.16
Sift	Benign	0.20	T
Sift4G	Benign	0.22	T
Vest4		0.36
MVP		0.50
MPC		0.0054
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.48
gMVP		0.33
Mutation Taster		=64/36	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: rs370194003; hg19: chr5-115168303;