19-16356948-A-G

Variant names:

• chr19-16356948-A-G
• rs875622
• NM_001258374.3:c.2587-1097T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001258374.3(EPS15L1):​c.2587-1097T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.69 in 151,956 control chromosomes in the GnomAD database, including 37,262 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.69 (37248 hom., cov: 31)
  • Exomes 𝑓: 0.74 (14 hom.)
• Consequence: EPS15L1 NM_001258374.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.245
• Publications: 14 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

ENSG00000280332 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.814 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPS15L1	NM_001258374.3	c.2587-1097T>C		intron_variant	Intron 23 of 23	ENST00000455140.7	NP_001245303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPS15L1	ENST00000455140.7	c.2587-1097T>C		intron_variant	Intron 23 of 23	2	NM_001258374.3	ENSP00000393313.1

Frequencies

GnomAD3 genomes AF: 0.691 AC: 104819 AN: 151784 Hom.: 37245 Cov.: 31

Gnomad AFR AF: 0.517

Gnomad AMI AF: 0.850

Gnomad AMR AF: 0.696

Gnomad ASJ AF: 0.873

Gnomad EAS AF: 0.657

Gnomad SAS AF: 0.835

Gnomad FIN AF: 0.691

Gnomad MID AF: 0.794

Gnomad NFE AF: 0.773

Gnomad OTH AF: 0.744

GnomAD4 exome AF: 0.741 AC: 40 AN: 54 Hom.: 14 Cov.: 0 AF XY: 0.750 AC XY: 21 AN XY: 28

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.813 AC: 13 AN: 16

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.731 AC: 19 AN: 26

Other (OTH) AF: 0.700 AC: 7 AN: 10

GnomAD4 genome AF: 0.690 AC: 104850 AN: 151902 Hom.: 37248 Cov.: 31 AF XY: 0.691 AC XY: 51288 AN XY: 74230

African (AFR) AF: 0.517 AC: 21380 AN: 41378

American (AMR) AF: 0.696 AC: 10623 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.873 AC: 3028 AN: 3470

East Asian (EAS) AF: 0.657 AC: 3385 AN: 5156

South Asian (SAS) AF: 0.835 AC: 4025 AN: 4820

European-Finnish (FIN) AF: 0.691 AC: 7291 AN: 10544

Middle Eastern (MID) AF: 0.799 AC: 235 AN: 294

European-Non Finnish (NFE) AF: 0.773 AC: 52536 AN: 67958

Other (OTH) AF: 0.746 AC: 1575 AN: 2110

Alfa AF: 0.749 Hom.: 141981

Bravo AF: 0.676

Asia WGS AF: 0.712 AC: 2474 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.8
DANN	Benign	0.81
PhyloP100		0.24
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs875622; hg19: chr19-16467759;