NM_001258374.3:c.2445G>C

Variant names:

• chr19-16361920-C-G
• rs776463184
• NM_001258374.3:c.2445G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001258374.3(EPS15L1):​c.2445G>C​(p.Gln815His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EPS15L1 NM_001258374.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.71
• Publications: 0 publications found

Genes affected

EPS15L1 (HGNC:24634): (epidermal growth factor receptor pathway substrate 15 like 1) Enables cadherin binding activity. Predicted to be involved in endocytosis and endosomal transport. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

EPS15L1 Gene-Disease associations (from GenCC):

• split hand-foot malformation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35281128).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001258374.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPS15L1	NM_001258374.3	MANE Select	c.2445G>C	p.Gln815His	missense	Exon 23 of 24	NP_001245303.1	Q9UBC2-2
	EPS15L1	NM_001438224.1		c.2493G>C	p.Gln831His	missense	Exon 24 of 25	NP_001425153.1
	EPS15L1	NM_021235.3		c.2445G>C	p.Gln815His	missense	Exon 23 of 23	NP_067058.1	Q9UBC2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPS15L1	ENST00000455140.7	TSL:2 MANE Select	c.2445G>C	p.Gln815His	missense	Exon 23 of 24	ENSP00000393313.1	Q9UBC2-2
	EPS15L1	ENST00000248070.10	TSL:1	c.2445G>C	p.Gln815His	missense	Exon 23 of 23	ENSP00000248070.5	Q9UBC2-1
	EPS15L1	ENST00000535753.6	TSL:1	c.*47G>C		3_prime_UTR	Exon 22 of 22	ENSP00000440103.1	Q9UBC2-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	2.0	M
PhyloP100		5.7
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.10
Sift	Benign	0.12	T
Sift4G	Uncertain	0.016	D
Polyphen		0.93	P
Vest4		0.55
MutPred		0.22		Gain of relative solvent accessibility (P = 0.2816)
MVP		0.45
MPC		0.38
ClinPred		0.92	D
GERP RS		4.6
PromoterAI		-0.0060	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.50
Mutation Taster		=61/39	polymorphism

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: rs776463184; hg19: chr19-16472731;