11-123606750-G-A

Variant names:

• chr11-123606750-G-A
• rs1952793461
• NM_001387025.1:c.1465G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001387025.1(GRAMD1B):​c.1465G>A​(p.Glu489Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,586 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: GRAMD1B NM_001387025.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.96

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRAMD1B	NM_001387025.1	c.1465G>A	p.Glu489Lys	missense_variant	Exon 11 of 20	ENST00000635736.2	NP_001373954.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRAMD1B	ENST00000635736.2	c.1465G>A	p.Glu489Lys	missense_variant	Exon 11 of 20	5	NM_001387025.1	ENSP00000490062.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461586 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727056

Gnomad4 AFR exome AF: 0.00

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000413 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1036G>A (p.E346K) alteration is located in exon 10 (coding exon 10) of the GRAMD1B gene. This alteration results from a G to A substitution at nucleotide position 1036, causing the glutamic acid (E) at amino acid position 346 to be replaced by a lysine (K). 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	0.87
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.075	T;T;T;.;T;T;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.70	T
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.4	.;.;.;D;D;D;D;D;.
REVEL	Uncertain	0.45
Sift	Uncertain	0.0040	.;.;.;D;D;D;D;D;.
Sift4G	Uncertain	0.021	.;.;.;D;D;D;D;D;.
Polyphen		1.0	.;.;.;.;.;D;.;.;.
Vest4		0.90, 0.92, 0.88, 0.79
MutPred		0.41		.;.;.;Gain of ubiquitination at E353 (P = 6e-04);.;.;.;.;.;
MVP		0.28
MPC		0.85
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.63
gMVP		0.58

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

Other links and lift over

dbSNP: rs1952793461; hg19: chr11-123477458;