chr7-20158817-G-A

Variant names:

• chr7-20158817-G-A
• rs975263
• NM_182762.4:c.1544C>T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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 0.29 (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
• Publications: 46 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
MACC1	NM_182762.4	c.1544C>T	p.Ser515Leu	missense_variant	Exon 5 of 7	ENST00000400331.10	NP_877439.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MACC1	ENST00000400331.10	c.1544C>T	p.Ser515Leu	missense_variant	Exon 5 of 7	2	NM_182762.4	ENSP00000383185.3
MACC1	ENST00000332878.8	c.1544C>T	p.Ser515Leu	missense_variant	Exon 3 of 5	1		ENSP00000328410.4
MACC1	ENST00000589011.1	c.1544C>T	p.Ser515Leu	missense_variant	Exon 3 of 5	5		ENSP00000466864.1

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

GnomAD2 exomes AF: 0.343 AC: 85974 AN: 250638 AF XY: 0.342

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 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

African (AFR) AF: 0.302 AC: 10105 AN: 33472

American (AMR) AF: 0.377 AC: 16871 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 8450 AN: 26130

East Asian (EAS) AF: 0.807 AC: 32017 AN: 39690

South Asian (SAS) AF: 0.450 AC: 38841 AN: 86250

European-Finnish (FIN) AF: 0.273 AC: 14585 AN: 53358

Middle Eastern (MID) AF: 0.291 AC: 1678 AN: 5766

European-Non Finnish (NFE) AF: 0.238 AC: 264438 AN: 1111904

Other (OTH) AF: 0.301 AC: 18153 AN: 60386

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

African (AFR) AF: 0.294 AC: 12191 AN: 41496

American (AMR) AF: 0.332 AC: 5059 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 1121 AN: 3466

East Asian (EAS) AF: 0.803 AC: 4151 AN: 5172

South Asian (SAS) AF: 0.468 AC: 2253 AN: 4812

European-Finnish (FIN) AF: 0.281 AC: 2966 AN: 10558

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.238 AC: 16181 AN: 67964

Other (OTH) AF: 0.282 AC: 595 AN: 2110

Alfa AF: 0.269 Hom.: 21438

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
LIST_S2	Benign	0.76	.;.;T
MetaRNN	Benign	0.0000010	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;L;L
PhyloP100		2.6
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
Mutation Taster		=100/0	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: rs975263; hg19: chr7-20198440; COSMIC: COSV60541702;