chr20-25013978-C-T

Variant names:

• chr20-25013978-C-T
• rs112683865
• NM_032501.4:c.1435G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032501.4(ACSS1):​c.1435G>A​(p.Val479Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,613,688 control chromosomes in the GnomAD database, including 126 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (65 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (61 hom.)
• Consequence: ACSS1 NM_032501.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.49
• Publications: 7 publications found

Genes affected

ACSS1 (HGNC:16091): (acyl-CoA synthetase short chain family member 1) This gene encodes a mitochondrial acetyl-CoA synthetase enzyme. A similar protein in mice plays an important role in the tricarboxylic acid cycle by catalyzing the conversion of acetate to acetyl CoA. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

ENSG00000306411 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01578024).
• BP6: Variant 20-25013978-C-T is Benign according to our data. Variant chr20-25013978-C-T is described in ClinVar as [Benign]. Clinvar id is 1258805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACSS1	NM_032501.4	c.1435G>A	p.Val479Ile	missense_variant	Exon 9 of 14	ENST00000323482.9	NP_115890.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACSS1	ENST00000323482.9	c.1435G>A	p.Val479Ile	missense_variant	Exon 9 of 14	1	NM_032501.4	ENSP00000316924.4
ACSS1	ENST00000432802.6	c.1435G>A	p.Val479Ile	missense_variant	Exon 9 of 12	2		ENSP00000388793.2
ACSS1	ENST00000537502.5	c.1072G>A	p.Val358Ile	missense_variant	Exon 8 of 13	2		ENSP00000439304.2
ENSG00000306411	ENST00000818190.1	n.504-4299C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2279 AN: 152216 Hom.: 64 Cov.: 33

Gnomad AFR AF: 0.0514

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.00447 AC: 1117 AN: 249968 AF XY: 0.00351

Gnomad AFR exome AF: 0.0536

Gnomad AMR exome AF: 0.00499

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000398

Gnomad OTH exome AF: 0.00360

GnomAD4 exome AF: 0.00192 AC: 2801 AN: 1461354 Hom.: 61 Cov.: 31 AF XY: 0.00178 AC XY: 1292 AN XY: 726952

African (AFR) AF: 0.0557 AC: 1865 AN: 33458

American (AMR) AF: 0.00526 AC: 235 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53292

Middle Eastern (MID) AF: 0.00928 AC: 53 AN: 5714

European-Non Finnish (NFE) AF: 0.000263 AC: 292 AN: 1111828

Other (OTH) AF: 0.00548 AC: 331 AN: 60372

GnomAD4 genome AF: 0.0150 AC: 2286 AN: 152334 Hom.: 65 Cov.: 33 AF XY: 0.0148 AC XY: 1105 AN XY: 74488

African (AFR) AF: 0.0514 AC: 2138 AN: 41576

American (AMR) AF: 0.00601 AC: 92 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68022

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.00536 Hom.: 51

Bravo AF: 0.0178

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0517 AC: 228

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00527 AC: 640

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000534

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	8.9
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	.;.;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.79	T;T;T
MetaRNN	Benign	0.016	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	.;M;M
PhyloP100		1.5
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.94	.;N;N
REVEL	Benign	0.11
Sift	Benign	0.036	.;D;D
Sift4G	Benign	0.11	T;T;T
Polyphen		0.92	.;.;P
Vest4		0.20
MVP		0.26
MPC		0.51
ClinPred		0.0098	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.47
Mutation Taster		=99/1	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: rs112683865; hg19: chr20-24994614;