19-48008723-A-G

Position:

• chr19-48008723-A-G

Variant summary

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

The NM_022142.5(ELSPBP1):​c.56A>G​(p.Tyr19Cys) 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 1,461,510 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ELSPBP1 NM_022142.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.16

Genes affected

ELSPBP1 (HGNC:14417): (epididymal sperm binding protein 1) The protein encoded by this gene belongs to the sperm-coating protein family of epididymal origin. This protein and its canine homolog are the first known examples of proteins with four tandemly arranged fibronectin type 2 (Fn2) domains in the Fn2-module protein family. [provided by RefSeq, Jul 2008]

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
ELSPBP1	NM_022142.5	c.56A>G	p.Tyr19Cys	missense_variant	2/7	ENST00000339841.7	NP_071425.3
ELSPBP1	XM_017027130.2	c.191A>G	p.Tyr64Cys	missense_variant	2/7		XP_016882619.1
ELSPBP1	XM_047439213.1	c.191A>G	p.Tyr64Cys	missense_variant	2/6		XP_047295169.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ELSPBP1	ENST00000339841.7	c.56A>G	p.Tyr19Cys	missense_variant	2/7	1	NM_022142.5	ENSP00000340660.2
ELSPBP1	ENST00000596043.5	c.56A>G	p.Tyr19Cys	missense_variant	2/5	3		ENSP00000470903.1
ELSPBP1	ENST00000597519.5	c.56A>G	p.Tyr19Cys	missense_variant	2/4	3		ENSP00000471690.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461510 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727048

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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 24, 2023

The c.56A>G (p.Y19C) alteration is located in exon 2 (coding exon 1) of the ELSPBP1 gene. This alteration results from a A to G substitution at nucleotide position 56, causing the tyrosine (Y) at amino acid position 19 to be replaced by a cysteine (C). 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	0.062
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	8.6
DANN	Benign	0.79
DEOGEN2	Benign	0.097	T;T;T;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.66	T;T;T;T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.7	D;.;.;.
REVEL	Benign	0.035
Sift	Benign	0.097	T;.;.;.
Sift4G	Benign	0.083	T;D;D;T
Polyphen		0.80	P;.;.;.
Vest4		0.17
MutPred		0.50		Loss of disorder (P = 0.0753);Loss of disorder (P = 0.0753);Loss of disorder (P = 0.0753);.;
MVP		0.54
MPC		0.15
ClinPred		0.45	T
GERP RS		-3.3
Varity_R		0.092

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.37		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1222264508; hg19: chr19-48511980; COSMIC: COSV60413752;