Variant 11-123608794-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001387025.1(GRAMD1B):c.1649G>A(p.Arg550His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000937 in 1,546,936 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. R550C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000095 ( 1 hom. )

Consequence

GRAMD1B
NM_001387025.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.07

Variant links:

Genes affected

GRAMD1B (HGNC:29214): (GRAM domain containing 1B) Predicted to enable cholesterol binding activity; cholesterol transfer activity; and phospholipid binding activity. Predicted to be involved in cellular response to cholesterol and cholesterol homeostasis. Located in endoplasmic reticulum membrane; endoplasmic reticulum-plasma membrane contact site; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

GRAMD1B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28616634).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GRAMD1B	NM_001387025.1 linkuse as main transcript	c.1649G>A	p.Arg550His	missense_variant	12/20	ENST00000635736.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GRAMD1B	ENST00000635736.2 linkuse as main transcript	c.1649G>A	p.Arg550His	missense_variant	12/20	5	NM_001387025.1	P1

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.0000294

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.0000884

AC:

AN:

158434

Hom.:

AF XY:

0.000109

AC XY:

AN XY:

82830

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000283

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000915

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000967

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000946

AC:

132

AN:

1394810

Hom.:

Cov.:

AF XY:

0.000112

AC XY:

AN XY:

687986

show subpopulations

Gnomad4 AFR exome

AF:

0.0000318

Gnomad4 AMR exome

AF:

0.000280

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.0000127

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000911

Gnomad4 OTH exome

AF:

0.000259

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00144

Alfa

AF:

0.000127

Hom.:

Bravo

AF:

0.000136

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000255

AC:

ESP6500EA

AF:

0.00

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 17, 2022

The c.1220G>A (p.R407H) alteration is located in exon 11 (coding exon 11) of the GRAMD1B gene. This alteration results from a G to A substitution at nucleotide position 1220, causing the arginine (R) at amino acid position 407 to be replaced by a histidine (H). 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

Benign

0.12

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.21

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.051

T;T;T;.;T;T;.;.;.;.

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.29

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.77

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.73

Polyphen

0.26, 1.0

.;.;.;.;.;B;.;.;.;D

Vest4

0.40, 0.46, 0.43, 0.40, 0.34

MVP

0.068

MPC

1.3

ClinPred

0.14

GERP RS

5.3

Varity_R

0.13

gMVP

0.68

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over