4-173371378-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003864.4(SAP30):c.196C>G(p.Leu66Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000259 in 1,557,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: SAP30 NM_003864.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.730

Genes affected

SAP30 (HGNC:10532): (Sin3A associated protein 30) Histone acetylation plays a key role in the regulation of eukaryotic gene expression. Histone acetylation and deacetylation are catalyzed by multisubunit complexes. The protein encoded by this gene is a component of the histone deacetylase complex, which includes SIN3, SAP18, HDAC1, HDAC2, RbAp46, RbAp48, and other polypeptides. This complex is active in deacetylating core histone octamers, but inactive in deacetylating nucleosomal histones. A pseudogene of this gene is located on chromosome 3. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07490784).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SAP30	NM_003864.4	c.196C>G	p.Leu66Val	missense_variant	1/4	ENST00000296504.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SAP30	ENST00000296504.4	c.196C>G	p.Leu66Val	missense_variant	1/4	1	NM_003864.4	P1

Frequencies

GnomAD3 genomes AF: 0.000232 AC: 35 AN: 151060 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

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: 0.000458

Gnomad OTH AF: 0.000482

GnomAD3 exomes AF: 0.000105 AC: 20 AN: 189826 Hom.: 0 AF XY: 0.000102 AC XY: 11 AN XY: 107710

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000335

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000262 AC: 369 AN: 1406838 Hom.: 0 Cov.: 31 AF XY: 0.000265 AC XY: 186 AN XY: 700650

Gnomad4 AFR exome AF: 0.0000682

Gnomad4 AMR exome AF: 0.0000245

Gnomad4 ASJ exome AF: 0.0000406

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000330

Gnomad4 OTH exome AF: 0.0000687

GnomAD4 genome AF: 0.000232 AC: 35 AN: 151060 Hom.: 0 Cov.: 31 AF XY: 0.000136 AC XY: 10 AN XY: 73778

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.0000658

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000458

Gnomad4 OTH AF: 0.000482

Alfa AF: 0.000261 Hom.: 0

Bravo AF: 0.000253

ESP6500AA AF: 0.000233 AC: 1

ESP6500EA AF: 0.000360 AC: 3

ExAC AF: 0.000102 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK:

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.196C>G (p.L66V) alteration is located in exon 1 (coding exon 1) of the SAP30 gene. This alteration results from a C to G substitution at nucleotide position 196, causing the leucine (L) at amino acid position 66 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.38

T

BayesDel_noAF

Benign

-0.49

Cadd

Benign

17

Dann

Benign

0.64

DEOGEN2

Benign

0.011

T

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.33

N

LIST_S2

Benign

0.77

T

M_CAP

Uncertain

0.16

D

MetaRNN

Benign

0.075

T

MetaSVM

Benign

-1.0

T

MutationAssessor

Benign

0.20

N

MutationTaster

Benign

0.87

D

PrimateAI

Pathogenic

0.92

D

PROVEAN

Benign

0.21

N

REVEL

Benign

0.045

Sift

Benign

0.72

T

Sift4G

Benign

0.69

T

Polyphen

0.0020

B

Vest4

0.14

MVP

0.13

MPC

0.64

ClinPred

0.057

T

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.062

gMVP

0.27

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

Publications

LitVar

Other links and lift over

dbSNP: rs201052655; hg19: chr4-174292529;