Genetic Variant MACC1:p.Ser515Trp (chr7-20158817-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_182762.4(MACC1):c.1544C>G(p.Ser515Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MACC1
NM_182762.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.59

Publications

46 publications found

Variant links:

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]

MACC1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20958021).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MACC1	NM_182762.4 link	c.1544C>G	p.Ser515Trp	missense_variant	Exon 5 of 7	ENST00000400331.10	NP_877439.3	Q6ZN28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MACC1	ENST00000400331.10 link	c.1544C>G	p.Ser515Trp	missense_variant	Exon 5 of 7	2	NM_182762.4	ENSP00000383185.3	Q6ZN28
MACC1	ENST00000332878.8 link	c.1544C>G	p.Ser515Trp	missense_variant	Exon 3 of 5	1		ENSP00000328410.4	Q6ZN28
MACC1	ENST00000589011.1 link	c.1544C>G	p.Ser515Trp	missense_variant	Exon 3 of 5	5		ENSP00000466864.1	Q6ZN28

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461800

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111990

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.039

T;T;T

Eigen

Benign

0.15

Eigen_PC

Benign

0.043

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.84

.;.;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.6

M;M;M

PhyloP100

2.6

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-2.6

D;D;.

REVEL

Benign

0.11

Sift

Benign

0.10

T;T;.

Sift4G

Benign

0.18

T;T;T

Polyphen

0.99

D;D;D

Vest4

0.39

MutPred

0.33

Loss of disorder (P = 0);Loss of disorder (P = 0);Loss of disorder (P = 0);

MVP

0.33

MPC

0.087

ClinPred

0.83

GERP RS

5.0

Varity_R

0.11

gMVP

0.34

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over