7-141555495-A-G

Variant names:

• chr7-141555495-A-G
• rs35269563
• NM_018238.4:c.29A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_018238.4(AGK):​c.29A>G​(p.Asn10Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000257 in 1,614,104 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: AGK NM_018238.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.06
• Publications: 1 publications found

Genes affected

AGK (HGNC:21869): (acylglycerol kinase) The protein encoded by this gene is a mitochondrial membrane protein involved in lipid and glycerolipid metabolism. The encoded protein is a lipid kinase that catalyzes the formation of phosphatidic and lysophosphatidic acids. Defects in this gene have been associated with mitochondrial DNA depletion syndrome 10. [provided by RefSeq, Feb 2012]

AGK Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Sengers syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cataract 38

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014673591).
• BP6: Variant 7-141555495-A-G is Benign according to our data. Variant chr7-141555495-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 214077.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00146 (222/152320) while in subpopulation AFR AF = 0.00515 (214/41580). AF 95% confidence interval is 0.00458. There are 1 homozygotes in GnomAd4. There are 110 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018238.4. 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
	AGK	NM_018238.4	MANE Select	c.29A>G	p.Asn10Ser	missense	Exon 2 of 16	NP_060708.1	Q53H12-1
	AGK	NM_001364948.3		c.29A>G	p.Asn10Ser	missense	Exon 2 of 15	NP_001351877.1	A0A3B3ISZ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGK	ENST00000649286.2	MANE Select	c.29A>G	p.Asn10Ser	missense	Exon 2 of 16	ENSP00000497280.1	Q53H12-1
	AGK	ENST00000492693.5	TSL:1	c.29A>G	p.Asn10Ser	missense	Exon 1 of 3	ENSP00000418789.1	Q53H12-2
	AGK	ENST00000912229.1		c.29A>G	p.Asn10Ser	missense	Exon 2 of 17	ENSP00000582288.1

Frequencies

GnomAD3 genomes AF: 0.00146 AC: 222 AN: 152202 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00516

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.000957

GnomAD2 exomes AF: 0.000314 AC: 79 AN: 251314 AF XY: 0.000228

Gnomad AFR exome AF: 0.00468

Gnomad AMR exome AF: 0.0000870

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: 0.000132 AC: 193 AN: 1461784 Hom.: 1 Cov.: 30 AF XY: 0.000105 AC XY: 76 AN XY: 727186

African (AFR) AF: 0.00505 AC: 169 AN: 33476

American (AMR) AF: 0.000112 AC: 5 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111970

Other (OTH) AF: 0.000281 AC: 17 AN: 60392

GnomAD4 genome AF: 0.00146 AC: 222 AN: 152320 Hom.: 1 Cov.: 32 AF XY: 0.00148 AC XY: 110 AN XY: 74488

African (AFR) AF: 0.00515 AC: 214 AN: 41580

American (AMR) AF: 0.000392 AC: 6 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000509 Hom.: 0

Bravo AF: 0.00175

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000428 AC: 52

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	AGK-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Sengers syndrome;C3553494:Cataract 38 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.28
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.060	T
Polyphen		0.98	D
Vest4		0.16
MVP		0.69
MPC		0.17
ClinPred		0.12	T
GERP RS		4.2
PromoterAI		0.0095	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.21
gMVP		0.60
Mutation Taster		=83/17	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: rs35269563; hg19: chr7-141255295;