8-105419177-A-G
Variant summary
Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_012082.4(ZFPM2):c.74A>G(p.Glu25Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,613,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E25K) has been classified as Uncertain significance.
Frequency
Consequence
NM_012082.4 missense
Scores
Clinical Significance
Conservation
Publications
- 46,XY sex reversal 9Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- diaphragmatic hernia 3Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
- tetralogy of fallotInheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
- 46,XY partial gonadal dysgenesisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_benign. The variant received -6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152202Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000443 AC: 11AN: 248440 AF XY: 0.0000371 show subpopulations
GnomAD4 exome AF: 0.0000315 AC: 46AN: 1461192Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22AN XY: 726844 show subpopulations
GnomAD4 genome AF: 0.0000919 AC: 14AN: 152320Hom.: 0 Cov.: 33 AF XY: 0.0000805 AC XY: 6AN XY: 74490 show subpopulations
ClinVar
Submissions by phenotype
46,XY sex reversal 9 Uncertain:1
This sequence change replaces glutamic acid with glycine at codon 25 of the ZFPM2 protein (p.Glu25Gly). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (rs371244942, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals affected with ZFPM2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at