chr11-123594078-G-A

Variant names:

• chr11-123594078-G-A
• rs118067934
• NM_001387025.1:c.685-4G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001387025.1(GRAMD1B):​c.685-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0248 in 1,603,964 control chromosomes in the GnomAD database, including 601 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.017 (30 hom., cov: 32)
  • Exomes 𝑓: 0.026 (571 hom.)
• Consequence: GRAMD1B NM_001387025.1 splice_region, intron
• Scores: Splicing: ADA: 0.00009174
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.304

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 11-123594078-G-A is Benign according to our data. Variant chr11-123594078-G-A is described in ClinVar as [Benign]. Clinvar id is 3056869.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0172 (2616/152214) while in subpopulation NFE AF = 0.027 (1834/68014). AF 95% confidence interval is 0.0259. There are 30 homozygotes in GnomAd4. There are 1176 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRAMD1B	NM_001387025.1	c.685-4G>A		splice_region_variant, intron_variant	Intron 4 of 19	ENST00000635736.2	NP_001373954.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRAMD1B	ENST00000635736.2	c.685-4G>A		splice_region_variant, intron_variant	Intron 4 of 19	5	NM_001387025.1	ENSP00000490062.1

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2617 AN: 152096 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.00594

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.0146

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0270

Gnomad OTH AF: 0.0173

GnomAD2 exomes AF: 0.0170 AC: 4232 AN: 249136 AF XY: 0.0170

Gnomad AFR exome AF: 0.00479

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.00348

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0136

Gnomad NFE exome AF: 0.0288

Gnomad OTH exome AF: 0.0155

GnomAD4 exome AF: 0.0256 AC: 37215 AN: 1451750 Hom.: 571 Cov.: 29 AF XY: 0.0249 AC XY: 17981 AN XY: 722976

Gnomad4 AFR exome AF: 0.00402 AC: 134 AN: 33320

Gnomad4 AMR exome AF: 0.0119 AC: 531 AN: 44714

Gnomad4 ASJ exome AF: 0.00399 AC: 104 AN: 26088

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39668

Gnomad4 SAS exome AF: 0.00386 AC: 332 AN: 86082

Gnomad4 FIN exome AF: 0.0151 AC: 807 AN: 53390

Gnomad4 NFE exome AF: 0.0309 AC: 34075 AN: 1102674

Gnomad4 Remaining exome AF: 0.0202 AC: 1214 AN: 60068

GnomAD4 genome AF: 0.0172 AC: 2616 AN: 152214 Hom.: 30 Cov.: 32 AF XY: 0.0158 AC XY: 1176 AN XY: 74414

Gnomad4 AFR AF: 0.00592 AC: 0.00592257 AN: 0.00592257

Gnomad4 AMR AF: 0.0128 AC: 0.0127518 AN: 0.0127518

Gnomad4 ASJ AF: 0.00519 AC: 0.00518732 AN: 0.00518732

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00249 AC: 0.00249273 AN: 0.00249273

Gnomad4 FIN AF: 0.0146 AC: 0.0146254 AN: 0.0146254

Gnomad4 NFE AF: 0.0270 AC: 0.026965 AN: 0.026965

Gnomad4 OTH AF: 0.0166 AC: 0.0166034 AN: 0.0166034

Alfa AF: 0.0234 Hom.: 79

Bravo AF: 0.0176

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0252

EpiControl AF: 0.0242

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

GRAMD1B-related disorder Benign:1

Jun 11, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.8
DANN	Benign	0.78
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000092
dbscSNV1_RF	Benign	0.012
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: rs118067934; hg19: chr11-123464786;