rs4721888

Positions:

• chr7-20161772-G-C

Variant summary

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

The NM_182762.4(MACC1):​c.91C>G​(p.Leu31Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0848 in 1,609,940 control chromosomes in the GnomAD database, including 7,224 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.069 (561 hom., cov: 33)
  • Exomes 𝑓: 0.086 (6663 hom.)
• Consequence: MACC1 NM_182762.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0620

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=0.006849557).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MACC1	NM_182762.4	c.91C>G	p.Leu31Val	missense_variant	4/7	ENST00000400331.10	NP_877439.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MACC1	ENST00000400331.10	c.91C>G	p.Leu31Val	missense_variant	4/7	2	NM_182762.4	ENSP00000383185	P1
MACC1	ENST00000332878.8	c.91C>G	p.Leu31Val	missense_variant	2/5	1		ENSP00000328410	P1
MACC1	ENST00000589011.1	c.91C>G	p.Leu31Val	missense_variant	2/5	5		ENSP00000466864	P1

Frequencies

GnomAD3 genomes AF: 0.0693 AC: 10531 AN: 151868 Hom.: 561 Cov.: 33

Gnomad AFR AF: 0.0182

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0704

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.278

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.0599

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0798

Gnomad OTH AF: 0.0705

GnomAD3 exomes AF: 0.0949 AC: 23797 AN: 250872 Hom.: 1632 AF XY: 0.0985 AC XY: 13358 AN XY: 135610

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.0601

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.279

Gnomad SAS exome AF: 0.138

Gnomad FIN exome AF: 0.0634

Gnomad NFE exome AF: 0.0807

Gnomad OTH exome AF: 0.0913

GnomAD4 exome AF: 0.0864 AC: 125919 AN: 1457954 Hom.: 6663 Cov.: 30 AF XY: 0.0883 AC XY: 64095 AN XY: 725470

Gnomad4 AFR exome AF: 0.0134

Gnomad4 AMR exome AF: 0.0621

Gnomad4 ASJ exome AF: 0.106

Gnomad4 EAS exome AF: 0.249

Gnomad4 SAS exome AF: 0.137

Gnomad4 FIN exome AF: 0.0623

Gnomad4 NFE exome AF: 0.0801

Gnomad4 OTH exome AF: 0.0930

GnomAD4 genome AF: 0.0693 AC: 10528 AN: 151986 Hom.: 561 Cov.: 33 AF XY: 0.0706 AC XY: 5245 AN XY: 74278

Gnomad4 AFR AF: 0.0182

Gnomad4 AMR AF: 0.0703

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.278

Gnomad4 SAS AF: 0.131

Gnomad4 FIN AF: 0.0599

Gnomad4 NFE AF: 0.0798

Gnomad4 OTH AF: 0.0722

Alfa AF: 0.0610 Hom.: 142

Bravo AF: 0.0659

TwinsUK AF: 0.0825 AC: 306

ALSPAC AF: 0.0745 AC: 287

ESP6500AA AF: 0.0209 AC: 92

ESP6500EA AF: 0.0791 AC: 680

ExAC AF: 0.0941 AC: 11425

Asia WGS AF: 0.181 AC: 631 AN: 3476

EpiCase AF: 0.0805

EpiControl AF: 0.0850

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.030
DANN	Benign	0.25
DEOGEN2	Benign	0.00064	T;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.44	.;.;T
MetaRNN	Benign	0.0068	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L;L;L
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.13	N;N;.
REVEL	Benign	0.045
Sift	Benign	0.72	T;T;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.049	B;B;B
Vest4		0.057
MPC		0.014
ClinPred		0.0018	T
GERP RS		-6.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.029
gMVP		0.11

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: rs4721888; hg19: chr7-20201395; COSMIC: COSV60541462; COSMIC: COSV60541462;