rs975263

chr7-20158817-G-Achr7-20158817-G-Cchr7-20158817-G-T

Variant summary

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

The NM_182762.4(MACC1):c.1544C>T(p.Ser515Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 1,613,700 control chromosomes in the GnomAD database, including 72,809 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.29 (7565 hom., cov: 32)
  • Exomes 𝑓: 0.28 (65244 hom.)
• Consequence: MACC1 NM_182762.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.59

Genes affected

MACC1 (HGNC:30215): (MET transcriptional regulator MACC1) MACC1 is a key regulator of the hepatocyte growth factor (HGF; MIM 142409)-HGF receptor (HGFR, or MET; MIM 164860) pathway, which is involved in cellular growth, epithelial-mesenchymal transition, angiogenesis, cell motility, invasiveness, and metastasis. Expression of MACC1 in colon cancer (MIM 114500) specimens is an independent prognostic indicator for metastasis formation and metastasis-free survival (Stein et al., 2009 [PubMed 19098908]).[supplied by OMIM, Mar 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0364147E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MACC1	NM_182762.4	c.1544C>T	p.Ser515Leu	missense_variant	5/7	ENST00000400331.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MACC1	ENST00000400331.10	c.1544C>T	p.Ser515Leu	missense_variant	5/7	2	NM_182762.4	P1
MACC1	ENST00000332878.8	c.1544C>T	p.Ser515Leu	missense_variant	3/5	1		P1
MACC1	ENST00000589011.1	c.1544C>T	p.Ser515Leu	missense_variant	3/5	5		P1

Frequencies

GnomAD3 genomes AF: 0.294 AC: 44646 AN: 151914 Hom.: 7563 Cov.: 32

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.803

Gnomad SAS AF: 0.468

Gnomad FIN AF: 0.281

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.281

GnomAD3 exomes AF: 0.343 AC: 85974 AN: 250638 Hom.: 17899 AF XY: 0.342 AC XY: 46410 AN XY: 135508

Gnomad AFR exome AF: 0.293

Gnomad AMR exome AF: 0.387

Gnomad ASJ exome AF: 0.326

Gnomad EAS exome AF: 0.818

Gnomad SAS exome AF: 0.453

Gnomad FIN exome AF: 0.284

Gnomad NFE exome AF: 0.245

Gnomad OTH exome AF: 0.295

GnomAD4 exome AF: 0.277 AC: 405138 AN: 1461668 Hom.: 65244 Cov.: 37 AF XY: 0.282 AC XY: 205255 AN XY: 727136

Gnomad4 AFR exome AF: 0.302

Gnomad4 AMR exome AF: 0.377

Gnomad4 ASJ exome AF: 0.323

Gnomad4 EAS exome AF: 0.807

Gnomad4 SAS exome AF: 0.450

Gnomad4 FIN exome AF: 0.273

Gnomad4 NFE exome AF: 0.238

Gnomad4 OTH exome AF: 0.301

GnomAD4 genome AF: 0.294 AC: 44684 AN: 152032 Hom.: 7565 Cov.: 32 AF XY: 0.302 AC XY: 22468 AN XY: 74320

Gnomad4 AFR AF: 0.294

Gnomad4 AMR AF: 0.332

Gnomad4 ASJ AF: 0.323

Gnomad4 EAS AF: 0.803

Gnomad4 SAS AF: 0.468

Gnomad4 FIN AF: 0.281

Gnomad4 NFE AF: 0.238

Gnomad4 OTH AF: 0.282

Alfa AF: 0.265 Hom.: 15168

Bravo AF: 0.298

TwinsUK AF: 0.233 AC: 864

ALSPAC AF: 0.237 AC: 912

ESP6500AA AF: 0.290 AC: 1276

ESP6500EA AF: 0.238 AC: 2048

ExAC AF: 0.339 AC: 41097

Asia WGS AF: 0.568 AC: 1978 AN: 3478

EpiCase AF: 0.243

EpiControl AF: 0.249

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	14
Dann	Benign	0.75
DEOGEN2	Benign	0.0076	T;T;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.24	N
MetaRNN	Benign	0.0000010	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;L;L
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.7	N;N;.
REVEL	Benign	0.12
Sift	Benign	0.55	T;T;.
Sift4G	Benign	0.69	T;T;T
Polyphen		0.014	B;B;B
Vest4		0.022
MPC		0.013
ClinPred		0.0077	T
GERP RS		5.0
Varity_R		0.085
gMVP		0.21

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: rs975263; hg19: chr7-20198440; COSMIC: COSV60541702;