chr5-126472269-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_023927.4(GRAMD2B):​c.347T>C​(p.Phe116Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

GRAMD2B
NM_023927.4 missense

Scores

13
4
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.44
Variant links:
Genes affected
GRAMD2B (HGNC:24911): (GRAM domain containing 2B) Enables identical protein binding activity. Located in cytoplasmic microtubule. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GRAMD2BNM_023927.4 linkc.347T>C p.Phe116Ser missense_variant Exon 4 of 14 ENST00000285689.8 NP_076416.2 Q96HH9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GRAMD2BENST00000285689.8 linkc.347T>C p.Phe116Ser missense_variant Exon 4 of 14 1 NM_023927.4 ENSP00000285689.3 Q96HH9-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251396
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135866
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000130
AC:
19
AN:
1461706
Hom.:
0
Cov.:
29
AF XY:
0.0000138
AC XY:
10
AN XY:
727168
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.0000144
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000624
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 29, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.392T>C (p.F131S) alteration is located in exon 4 (coding exon 4) of the GRAMD3 gene. This alteration results from a T to C substitution at nucleotide position 392, causing the phenylalanine (F) at amino acid position 131 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.46
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
.;D;D;D;.;.;.;.
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.97
D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.50
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
PrimateAI
Uncertain
0.68
T
PROVEAN
Pathogenic
-7.2
D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D;D;D
Polyphen
1.0
.;.;D;.;.;.;.;.
Vest4
0.99
MutPred
0.93
.;.;Gain of disorder (P = 0.0245);.;.;.;.;.;
MVP
0.98
MPC
1.1
ClinPred
1.0
D
GERP RS
5.9
Varity_R
0.94
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs746959753; hg19: chr5-125807961; API