NM_001387025.1:c.1160C>G

Variant names:

• chr11-123603535-C-G
• rs1565448169
• NM_001387025.1:c.1160C>G

Variant summary

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

The NM_001387025.1(GRAMD1B):​c.1160C>G​(p.Thr387Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,451,486 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: GRAMD1B NM_001387025.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.75
• 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: 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.1160C>G	p.Thr387Arg	missense	Exon 9 of 20	NP_001373954.1	A0A1B0GUD6
	GRAMD1B	NM_001387024.1		c.1160C>G	p.Thr387Arg	missense	Exon 9 of 20	NP_001373953.1
	GRAMD1B	NM_001387026.1		c.1157C>G	p.Thr386Arg	missense	Exon 9 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.1160C>G	p.Thr387Arg	missense	Exon 9 of 20	ENSP00000490062.1	A0A1B0GUD6
	GRAMD1B	ENST00000529750.5	TSL:1	c.731C>G	p.Thr244Arg	missense	Exon 8 of 20	ENSP00000436500.1	Q3KR37-1
	GRAMD1B	ENST00000534764.1	TSL:1	c.719C>G	p.Thr240Arg	missense	Exon 8 of 12	ENSP00000434214.1	E9PRD6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1451486 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 722770

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33276

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 86072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102534

Other (OTH) AF: 0.0000666 AC: 4 AN: 60046

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000012246), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

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	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-1.1	T
PhyloP100		7.8
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.19
Sift	Benign	0.32	T
Sift4G	Benign	0.13	T
Polyphen		0.93	P
Vest4		0.74
MutPred		0.33		Loss of glycosylation at T251 (P = 0.0235)
MVP		0.12
MPC		0.98
ClinPred		0.94	D
GERP RS		5.2
Varity_R		0.30
gMVP		0.70
Mutation Taster		=35/65	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: rs1565448169; hg19: chr11-123474243;