chr11-123605383-A-G

Variant names:

• chr11-123605383-A-G
• rs1455008458
• NM_001387025.1:c.1228A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001387025.1(GRAMD1B):​c.1228A>G​(p.Ile410Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,284 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GRAMD1B NM_001387025.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.90
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037935972).

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.1228A>G	p.Ile410Val	missense	Exon 10 of 20	NP_001373954.1	A0A1B0GUD6
	GRAMD1B	NM_001387024.1		c.1228A>G	p.Ile410Val	missense	Exon 10 of 20	NP_001373953.1
	GRAMD1B	NM_001387026.1		c.1225A>G	p.Ile409Val	missense	Exon 10 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.1228A>G	p.Ile410Val	missense	Exon 10 of 20	ENSP00000490062.1	A0A1B0GUD6
	GRAMD1B	ENST00000529750.5	TSL:1	c.799A>G	p.Ile267Val	missense	Exon 9 of 20	ENSP00000436500.1	Q3KR37-1
	GRAMD1B	ENST00000534764.1	TSL:1	c.787A>G	p.Ile263Val	missense	Exon 9 of 12	ENSP00000434214.1	E9PRD6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248778 AF XY: 0.00000741

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461102 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726860

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111438

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74330

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	18
DANN	Benign	0.83
DEOGEN2	Benign	0.0053	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.9
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.032
Sift	Benign	0.58	T
Sift4G	Benign	0.63	T
Polyphen		0.0	B
Vest4		0.038
MutPred		0.16		Loss of glycosylation at S273 (P = 0.1108)
MVP		0.043
MPC		0.31
ClinPred		0.15	T
GERP RS		2.7
Varity_R		0.023
gMVP		0.18
Mutation Taster		=94/6	polymorphism

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: rs1455008458; hg19: chr11-123476091;