rs147599832

chrX-68839969-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004429.5(EFNB1):c.509C>T(p.Ala170Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,210,488 control chromosomes in the GnomAD database, including 12 homozygotes. There are 339 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (4 hom., 163 hem., cov: 24)
  • Exomes 𝑓: 0.00056 (8 hom. 176 hem.)
• Consequence: EFNB1 NM_004429.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.26

Genes affected

EFNB1 (HGNC:3226): (ephrin B1) The protein encoded by this gene is a type I membrane protein and a ligand of Eph-related receptor tyrosine kinases. It may play a role in cell adhesion and function in the development or maintenance of the nervous system. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a topological_domain Extracellular (size 209) in uniprot entity EFNB1_HUMAN there are 35 pathogenic changes around while only 6 benign (85%) in NM_004429.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0074879825).
• BP6: Variant X-68839969-C-T is Benign according to our data. Variant chrX-68839969-C-T is described in ClinVar as [Benign]. Clinvar id is 376763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-68839969-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00533 (600/112482) while in subpopulation AFR AF= 0.0184 (570/30983). AF 95% confidence interval is 0.0171. There are 4 homozygotes in gnomad4. There are 163 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFNB1	NM_004429.5	c.509C>T	p.Ala170Val	missense_variant	4/5	ENST00000204961.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFNB1	ENST00000204961.5	c.509C>T	p.Ala170Val	missense_variant	4/5	1	NM_004429.5	P1

Frequencies

GnomAD3 genomes AF: 0.00535 AC: 601 AN: 112429 Hom.: 4 Cov.: 24 AF XY: 0.00471 AC XY: 163 AN XY: 34587

Gnomad AFR AF: 0.0185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00233

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: 0.0000188

Gnomad OTH AF: 0.00265

GnomAD3 exomes AF: 0.00151 AC: 275 AN: 182215 Hom.: 3 AF XY: 0.00108 AC XY: 72 AN XY: 66807

Gnomad AFR exome AF: 0.0181

Gnomad AMR exome AF: 0.00132

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000443

GnomAD4 exome AF: 0.000557 AC: 612 AN: 1098006 Hom.: 8 Cov.: 32 AF XY: 0.000484 AC XY: 176 AN XY: 363366

Gnomad4 AFR exome AF: 0.0189

Gnomad4 AMR exome AF: 0.00142

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000831

Gnomad4 OTH exome AF: 0.00115

GnomAD4 genome AF: 0.00533 AC: 600 AN: 112482 Hom.: 4 Cov.: 24 AF XY: 0.00470 AC XY: 163 AN XY: 34650

Gnomad4 AFR AF: 0.0184

Gnomad4 AMR AF: 0.00233

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00261

Alfa AF: 0.000484 Hom.: 11

Bravo AF: 0.00701

ESP6500AA AF: 0.0146 AC: 56

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00188 AC: 228

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 25, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 09, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	19
Dann	Benign	0.97
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0075	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.29
Sift	Benign	0.11	T
Sift4G	Benign	0.49	T
Polyphen		0.42	B
Vest4		0.29
MVP		0.87
MPC		0.70
ClinPred		0.025	T
GERP RS		5.1
Varity_R		0.22
gMVP		0.86

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

LitVar

Other links and lift over

dbSNP: rs147599832; hg19: chrX-68059812; COSMIC: COSV99079543;