chr19-35013669-C-T

Variant names:

• chr19-35013669-C-T
• rs199949479
• NM_020895.5:c.848C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_020895.5(GRAMD1A):​c.848C>T​(p.Ala283Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,611,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: GRAMD1A NM_020895.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.24
• Publications: 1 publications found

Genes affected

GRAMD1A (HGNC:29305): (GRAM domain containing 1A) Predicted to enable cholesterol binding activity and cholesterol transfer activity. Predicted to be involved in cellular response to cholesterol. Located in cytosol; organelle membrane contact site; and plasma membrane. Is extrinsic component of cytoplasmic side of plasma membrane and intrinsic component of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.040299535).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020895.5. 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
	GRAMD1A	NM_020895.5	MANE Select	c.848C>T	p.Ala283Val	missense	Exon 9 of 20	NP_065946.2	Q96CP6-1
	GRAMD1A	NM_001320036.2		c.1109C>T	p.Ala370Val	missense	Exon 10 of 20	NP_001306965.1
	GRAMD1A	NM_001320034.2		c.848C>T	p.Ala283Val	missense	Exon 9 of 19	NP_001306963.1	Q96CP6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GRAMD1A	ENST00000317991.10	TSL:1 MANE Select	c.848C>T	p.Ala283Val	missense	Exon 9 of 20	ENSP00000441032.1	Q96CP6-1
	GRAMD1A	ENST00000599564.5	TSL:5	c.1109C>T	p.Ala370Val	missense	Exon 10 of 20	ENSP00000470220.1	M0QZ12
	GRAMD1A	ENST00000942874.1		c.848C>T	p.Ala283Val	missense	Exon 9 of 20	ENSP00000612933.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152142 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000527 AC: 13 AN: 246744 AF XY: 0.0000373

Gnomad AFR exome AF: 0.000785

Gnomad AMR exome AF: 0.0000291

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: 0.0000336 AC: 49 AN: 1459414 Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21 AN XY: 725856

African (AFR) AF: 0.00114 AC: 38 AN: 33430

American (AMR) AF: 0.0000448 AC: 2 AN: 44596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26022

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5206

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110898

Other (OTH) AF: 0.000133 AC: 8 AN: 60262

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152260 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74450

African (AFR) AF: 0.000843 AC: 35 AN: 41536

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000110 Hom.: 0

Bravo AF: 0.000272

ESP6500AA AF: 0.000242 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000661 AC: 8

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	Benign	0.085
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0099	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.88	T
PhyloP100		2.2
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.78	N
REVEL	Benign	0.051
Sift	Benign	0.26	T
Sift4G	Benign	0.32	T
Polyphen		0.15	B
Vest4		0.51
MVP		0.043
MPC		0.42
ClinPred		0.032	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.084
gMVP		0.28
Mutation Taster		=80/20	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: rs199949479; hg19: chr19-35504573;