16-30700867-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_006662.3(SRCAP):c.43C>G(p.Leu15Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L15L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SRCAP
NM_006662.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.53

Variant links:

Genes affected

SRCAP (HGNC:16974): (Snf2 related CREBBP activator protein) This gene encodes the core catalytic component of the multiprotein chromatin-remodeling SRCAP complex. The encoded protein is an ATPase that is necessary for the incorporation of the histone variant H2A.Z into nucleosomes. It can function as a transcriptional activator in Notch-mediated, CREB-mediated and steroid receptor-mediated transcription. Mutations in this gene cause Floating-Harbor syndrome, a rare disorder characterized by short stature, language deficits and dysmorphic facial features. [provided by RefSeq, Feb 2012]

SRCAP links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, SRCAP

BP4

Computational evidence support a benign effect (MetaRNN=0.19587582).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRCAP	NM_006662.3 linkuse as main transcript	c.43C>G	p.Leu15Val	missense_variant	3/34	ENST00000262518.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRCAP	ENST00000262518.9 linkuse as main transcript	c.43C>G	p.Leu15Val	missense_variant	3/34	2	NM_006662.3	P1	Q6ZRS2-1
SRCAP	ENST00000411466.7 linkuse as main transcript	c.43C>G	p.Leu15Val	missense_variant	3/34	3		P1	Q6ZRS2-1
SRCAP	ENST00000706321.1 linkuse as main transcript	c.43C>G	p.Leu15Val	missense_variant	3/34			P1	Q6ZRS2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000804

AC:

AN:

248864

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135076

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 15, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SRCAP-related conditions. This variant is present in population databases (rs371783481, ExAC 0.006%). This sequence change replaces leucine with valine at codon 15 of the SRCAP protein (p.Leu15Val). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and valine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Uncertain

0.031

BayesDel_noAF

Benign

-0.10

Cadd

Benign

Dann

Benign

0.90

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.045

MetaRNN

Benign

0.20

T;T

MetaSVM

Uncertain

-0.10

MutationTaster

Benign

0.98

N;N;N

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.6

D;N

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;T

Polyphen

0.99

.;D

Vest4

0.16

MutPred

0.26

Gain of catalytic residue at L15 (P = 0.0213);Gain of catalytic residue at L15 (P = 0.0213);

MVP

0.12

MPC

0.011

ClinPred

0.43

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.15

gMVP

0.33

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over