11-123606742-A-T

Variant names:

• chr11-123606742-A-T
• rs377539345
• NM_001387025.1:c.1457A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001387025.1(GRAMD1B):​c.1457A>T​(p.Asn486Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N486S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GRAMD1B NM_001387025.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.29
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387025.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRAMD1B	NM_001387025.1	MANE Select	c.1457A>T	p.Asn486Ile	missense	Exon 11 of 20	NP_001373954.1	A0A1B0GUD6
	GRAMD1B	NM_001387024.1		c.1457A>T	p.Asn486Ile	missense	Exon 11 of 20	NP_001373953.1
	GRAMD1B	NM_001387026.1		c.1454A>T	p.Asn485Ile	missense	Exon 11 of 20	NP_001373955.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRAMD1B	ENST00000635736.2	TSL:5 MANE Select	c.1457A>T	p.Asn486Ile	missense	Exon 11 of 20	ENSP00000490062.1	A0A1B0GUD6
	GRAMD1B	ENST00000529750.5	TSL:1	c.1028A>T	p.Asn343Ile	missense	Exon 10 of 20	ENSP00000436500.1	Q3KR37-1
	GRAMD1B	ENST00000534764.1	TSL:1	c.1016A>T	p.Asn339Ile	missense	Exon 10 of 12	ENSP00000434214.1	E9PRD6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.081	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-1.0	T
PhyloP100		9.3
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.41
Sift	Benign	0.10	T
Sift4G	Benign	0.22	T
Polyphen		0.84	P
Vest4		0.84
MutPred		0.29		Loss of disorder (P = 0.0644)
MVP		0.16
MPC		0.97
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.48
gMVP		0.57
Mutation Taster		=21/79	disease causing

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

Other links and lift over

dbSNP: rs377539345; hg19: chr11-123477450;