10-112164573-G-T

Variant names:

• chr10-112164573-G-T
• rs73365184
• NM_001244949.2:c.1259C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001244949.2(GPAM):​c.1259C>A​(p.Ala420Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,454,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A420V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GPAM NM_001244949.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.99
• Publications: 0 publications found

Genes affected

GPAM (HGNC:24865): (glycerol-3-phosphate acyltransferase, mitochondrial) This gene encodes a mitochondrial enzyme which prefers saturated fatty acids as its substrate for the synthesis of glycerolipids. This metabolic pathway's first step is catalyzed by the encoded enzyme. Two forms for this enzyme exist, one in the mitochondria and one in the endoplasmic reticulum. Two alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19106853).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001244949.2. 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
	GPAM	NM_001244949.2	MANE Select	c.1259C>A	p.Ala420Asp	missense	Exon 13 of 22	NP_001231878.1	Q9HCL2
	GPAM	NM_020918.6		c.1259C>A	p.Ala420Asp	missense	Exon 13 of 22	NP_065969.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPAM	ENST00000348367.9	TSL:1 MANE Select	c.1259C>A	p.Ala420Asp	missense	Exon 13 of 22	ENSP00000265276.4	Q9HCL2
	GPAM	ENST00000369425.5	TSL:1	c.1259C>A	p.Ala420Asp	missense	Exon 13 of 19	ENSP00000358433.1	Q5VW52
	GPAM	ENST00000964625.1		c.1259C>A	p.Ala420Asp	missense	Exon 13 of 22	ENSP00000634684.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454818 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 724274

⚠️ 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: 33290

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 86132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1105706

Other (OTH) AF: 0.00 AC: 0 AN: 60116

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.079
Eigen_PC	Benign	-0.045
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.12
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.054	T
Polyphen		0.16	B
Vest4		0.29
MutPred		0.40		Gain of relative solvent accessibility (P = 0.0215)
MVP		0.59
MPC		0.54
ClinPred		0.73	D
GERP RS		4.3
Varity_R		0.25
gMVP		0.45
Mutation Taster		=87/13	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: rs73365184; hg19: chr10-113924331;