chr16-30700867-C-G

Position:

• chr16-30700867-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SRCAP NM_006662.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SRCAP. . Gene score misZ 2.1272 (greater than the threshold 3.09). Trascript score misZ 3.6253 (greater than threshold 3.09). GenCC has associacion of gene with developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities, Floating-Harbor syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19587582).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRCAP	NM_006662.3	c.43C>G	p.Leu15Val	missense_variant	3/34	ENST00000262518.9	NP_006653.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRCAP	ENST00000262518.9	c.43C>G	p.Leu15Val	missense_variant	3/34	2	NM_006662.3	ENSP00000262518	P1
SRCAP	ENST00000411466.7	c.43C>G	p.Leu15Val	missense_variant	3/34	3		ENSP00000405186	P1
SRCAP	ENST00000706321.1	c.43C>G	p.Leu15Val	missense_variant	3/34			ENSP00000516346	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000804 AC: 2 AN: 248864 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135076

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: 1 AN: 1461842 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727226

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.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	18
DANN	Benign	0.90
DEOGEN2	Benign	0.033	.;T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	0.69	.;N
MutationTaster	Benign	0.98	N;N;N
PrimateAI	Uncertain	0.70	T
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	T
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

Other links and lift over

dbSNP: rs371783481; hg19: chr16-30712188;