2-211383773-C-G
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2
The NM_005235.3(ERBB4):āc.3769G>Cā(p.Asp1257His) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Consequence
NM_005235.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ERBB4 | ENST00000342788.9 | c.3769G>C | p.Asp1257His | missense_variant | Exon 28 of 28 | 1 | NM_005235.3 | ENSP00000342235.4 | ||
ERBB4 | ENST00000436443.5 | c.3721G>C | p.Asp1241His | missense_variant | Exon 27 of 27 | 1 | ENSP00000403204.1 | |||
ERBB4 | ENST00000260943.11 | c.3691G>C | p.Asp1231His | missense_variant | Exon 27 of 27 | 5 | ENSP00000260943.7 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152108Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000518 AC: 13AN: 251126Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135708
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461836Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727210
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152108Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74304
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: ERBB4 c.3769G>C (p.Asp1257His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251126 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ERBB4 causing Amyotrophic Lateral Sclerosis Type 19, allowing no conclusion about variant significance. c.3769G>C has been reported in the literature in an individual affected with Amyotrophic Lateral Sclerosis Type 19 but has also been detected in a control subject (Wang_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Amyotrophic Lateral Sclerosis Type 19. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 35481267). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at