NM_004444.5:c.2915C>A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_004444.5(EPHB4):c.2915C>A(p.Ala972Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,592,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A972A) has been classified as Likely benign.
Frequency
Consequence
NM_004444.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EPHB4 | ENST00000358173.8 | c.2915C>A | p.Ala972Asp | missense_variant | Exon 17 of 17 | 1 | NM_004444.5 | ENSP00000350896.3 | ||
EPHB4 | ENST00000360620.7 | c.2759C>A | p.Ala920Asp | missense_variant | Exon 16 of 16 | 1 | ENSP00000353833.3 | |||
EPHB4 | ENST00000487222.5 | n.4116C>A | non_coding_transcript_exon_variant | Exon 16 of 16 | 1 | |||||
EPHB4 | ENST00000616502 | c.*1380C>A | 3_prime_UTR_variant | Exon 14 of 14 | 5 | ENSP00000482702.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000139 AC: 2AN: 1440120Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1AN XY: 713712
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74324
ClinVar
Submissions by phenotype
EPHB4-associated vascular malformation spectrum Uncertain:1
This sequence change in EPHB4 is predicted to replace alanine with aspartic acid at codon 972, p.(Ala972Asp). The alanine residue is moderately conserved (61/96 vertebrates, UCSC), and is not located in an annotated domain. There is a large physicochemical difference between alanine and aspartic acid. This variant is present in a single individual in the East Asian population (1/5,176 alleles) in the population database gnomAD v3.1. To our knowledge, this variant has not been reported in the literature. Multiple lines of computational evidence predict a benign effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2_Supporting, BP4. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at