rs191981781

Variant names:

• chr11-123606675-A-G
• rs191981781
• NM_001387025.1:c.1390A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001387025.1(GRAMD1B):​c.1390A>G​(p.Ile464Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,613,494 control chromosomes in the GnomAD database, including 20 homozygotes. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00088 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (18 hom.)
• Consequence: GRAMD1B NM_001387025.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.54
• Publications: 6 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061227083).
• BP6: Variant 11-123606675-A-G is Benign according to our data. Variant chr11-123606675-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2642483.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 gene

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.1390A>G	p.Ile464Val	missense	Exon 11 of 20	NP_001373954.1	A0A1B0GUD6
	GRAMD1B	NM_001387024.1		c.1390A>G	p.Ile464Val	missense	Exon 11 of 20	NP_001373953.1
	GRAMD1B	NM_001387026.1		c.1387A>G	p.Ile463Val	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.1390A>G	p.Ile464Val	missense	Exon 11 of 20	ENSP00000490062.1	A0A1B0GUD6
	GRAMD1B	ENST00000529750.5	TSL:1	c.961A>G	p.Ile321Val	missense	Exon 10 of 20	ENSP00000436500.1	Q3KR37-1
	GRAMD1B	ENST00000534764.1	TSL:1	c.949A>G	p.Ile317Val	missense	Exon 10 of 12	ENSP00000434214.1	E9PRD6

Frequencies

GnomAD3 genomes AF: 0.000887 AC: 135 AN: 152172 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00177 AC: 439 AN: 248212 AF XY: 0.00198

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.0176

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000719

Gnomad OTH exome AF: 0.00348

GnomAD4 exome AF: 0.00105 AC: 1533 AN: 1461204 Hom.: 18 Cov.: 32 AF XY: 0.00127 AC XY: 921 AN XY: 726800

African (AFR) AF: 0.000149 AC: 5 AN: 33474

American (AMR) AF: 0.000224 AC: 10 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.0186 AC: 487 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00522 AC: 449 AN: 86004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.0123 AC: 71 AN: 5768

European-Non Finnish (NFE) AF: 0.000324 AC: 360 AN: 1111720

Other (OTH) AF: 0.00250 AC: 151 AN: 60362

GnomAD4 genome AF: 0.000880 AC: 134 AN: 152290 Hom.: 2 Cov.: 32 AF XY: 0.000873 AC XY: 65 AN XY: 74464

African (AFR) AF: 0.0000722 AC: 3 AN: 41566

American (AMR) AF: 0.000653 AC: 10 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 55 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00602 AC: 29 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68014

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00130 Hom.: 1

Bravo AF: 0.000744

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000843 AC: 7

ExAC AF: 0.00174 AC: 210

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.00190

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.0018	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.5
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.021
Sift	Benign	0.61	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.10
MVP		0.043
MPC		0.31
ClinPred		0.025	T
GERP RS		2.7
Varity_R		0.025
gMVP		0.17
Mutation Taster		=100/0	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: rs191981781; hg19: chr11-123477383; COSMIC: COSV59208616; COSMIC: COSV59208616;