chr4-74449169-C-T

Position:

• chr4-74449169-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000395748.8(AREG):​c.433C>T​(p.Pro145Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: AREG ENST00000395748.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.12

Genes affected

AREG (HGNC:651): (amphiregulin) The protein encoded by this gene is a member of the epidermal growth factor family. It is an autocrine growth factor as well as a mitogen for astrocytes, Schwann cells and fibroblasts. It is related to epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha). The protein interacts with the EGF/TGF-alpha receptor to promote the growth of normal epithelial cells, and it inhibits the growth of certain aggressive carcinoma cell lines. It also functions in mammary gland, oocyte and bone tissue development. This gene is associated with a psoriasis-like skin phenotype, and is also associated with other pathological disorders, including various types of cancers and inflammatory conditions. [provided by RefSeq, Apr 2014]

AREG (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AREG	NM_001657.4	c.433C>T	p.Pro145Ser	missense_variant	3/6	ENST00000395748.8	NP_001648.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AREG	ENST00000395748.8	c.433C>T	p.Pro145Ser	missense_variant	3/6	1	NM_001657.4	ENSP00000379097.3
AREG	ENST00000502307.1	c.433C>T	p.Pro145Ser	missense_variant	3/5	5		ENSP00000421414.1
AREG	ENST00000511560.1	n.531C>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2023

The c.433C>T (p.P145S) alteration is located in exon 3 (coding exon 3) of the AREG gene. This alteration results from a C to T substitution at nucleotide position 433, causing the proline (P) at amino acid position 145 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-7.3	D;D
REVEL	Benign	0.22
Sift	Uncertain	0.026	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		0.99	D;.
Vest4		0.37
MutPred		0.49		Loss of catalytic residue at P145 (P = 0.0083);Loss of catalytic residue at P145 (P = 0.0083);
MVP		0.36
MPC		3.3
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.45
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-75314886;