rs104894804

chrX-68838684-C-GchrX-68838684-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_004429.5(EFNB1):c.196C>G(p.Arg66Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 1,209,967 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: EFNB1 NM_004429.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.54

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain Ephrin RBD (size 134) in uniprot entity EFNB1_HUMAN there are 34 pathogenic changes around while only 3 benign (92%) in NM_004429.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EFNB1	NM_004429.5	c.196C>G	p.Arg66Gly	missense_variant	2/5	ENST00000204961.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EFNB1	ENST00000204961.5	c.196C>G	p.Arg66Gly	missense_variant	2/5	1	NM_004429.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000890 AC: 1 AN: 112339 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34481

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097628 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363006

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000890 AC: 1 AN: 112339 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34481

Gnomad4 AFR AF: 0.0000324

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.090
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	0.51	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.010	D
Polyphen		0.39	B
Vest4		0.46
MutPred		0.65		Gain of sheet (P = 0.0827);
MVP		0.99
MPC		0.72
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.87
gMVP		0.95

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: rs104894804; hg19: chrX-68058527;