19-16361784-T-C

Variant names:

• chr19-16361784-T-C
• rs144623166
• NM_001258374.3:c.2581A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001258374.3(EPS15L1):​c.2581A>G​(p.Thr861Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000615 in 1,612,058 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00064 (2 hom.)
• Consequence: EPS15L1 NM_001258374.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.597
• Publications: 3 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019196361).
• BS2: High AC in GnomAd4 at 63 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPS15L1	NM_001258374.3	c.2581A>G	p.Thr861Ala	missense_variant	Exon 23 of 24	ENST00000455140.7	NP_001245303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPS15L1	ENST00000455140.7	c.2581A>G	p.Thr861Ala	missense_variant	Exon 23 of 24	2	NM_001258374.3	ENSP00000393313.1

Frequencies

GnomAD3 genomes AF: 0.000416 AC: 63 AN: 151542 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000985

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000633

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000326 AC: 81 AN: 248552 AF XY: 0.000320

Gnomad AFR exome AF: 0.000251

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.000596

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000635 AC: 928 AN: 1460398 Hom.: 2 Cov.: 33 AF XY: 0.000578 AC XY: 420 AN XY: 726360

African (AFR) AF: 0.000209 AC: 7 AN: 33458

American (AMR) AF: 0.000225 AC: 10 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 85934

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.000794 AC: 883 AN: 1111412

Other (OTH) AF: 0.000414 AC: 25 AN: 60346

GnomAD4 genome AF: 0.000415 AC: 63 AN: 151660 Hom.: 0 Cov.: 32 AF XY: 0.000391 AC XY: 29 AN XY: 74096

African (AFR) AF: 0.000121 AC: 5 AN: 41314

American (AMR) AF: 0.000984 AC: 15 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10504

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000634 AC: 43 AN: 67876

Other (OTH) AF: 0.00 AC: 0 AN: 2096

Alfa AF: 0.000517 Hom.: 0

Bravo AF: 0.000366

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000329 AC: 40

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2581A>G (p.T861A) alteration is located in exon 23 (coding exon 23) of the EPS15L1 gene. This alteration results from a A to G substitution at nucleotide position 2581, causing the threonine (T) at amino acid position 861 to be replaced by an alanine (A). 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	Benign	0.063
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.031	.;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.64	T;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.019	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.69	N;N
PhyloP100		0.60
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.17	N;N
REVEL	Benign	0.085
Sift	Benign	0.38	T;T
Sift4G	Benign	0.88	T;T
Polyphen		0.0	.;B
Vest4		0.14
MVP		0.39
MPC		0.085
ClinPred		0.013	T
GERP RS		2.9
PromoterAI		0.040	Neutral
Varity_R		0.087
gMVP		0.12
Mutation Taster		=88/12	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: rs144623166; hg19: chr19-16472595; COSMIC: COSV106083813; COSMIC: COSV106083813;