rs150246733

Positions:

• chr16-30722724-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006662.3(SRCAP):​c.3868A>G​(p.Ser1290Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000782 in 1,612,270 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00084 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (7 hom.)
• Consequence: SRCAP NM_006662.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.42

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 Benign. Variant got -19 ACMG points.

• 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=0.0070759654).
• BP6: Variant 16-30722724-A-G is Benign according to our data. Variant chr16-30722724-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 218689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-30722724-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000776 (1133/1460638) while in subpopulation MID AF= 0.0123 (71/5762). AF 95% confidence interval is 0.01. There are 7 homozygotes in gnomad4_exome. There are 587 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 127 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRCAP	NM_006662.3	c.3868A>G	p.Ser1290Gly	missense_variant	23/34	ENST00000262518.9	NP_006653.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRCAP	ENST00000262518.9	c.3868A>G	p.Ser1290Gly	missense_variant	23/34	2	NM_006662.3	ENSP00000262518	P1
SRCAP	ENST00000411466.7	c.3868A>G	p.Ser1290Gly	missense_variant	23/34	3		ENSP00000405186	P1
SRCAP	ENST00000706321.1	c.3868A>G	p.Ser1290Gly	missense_variant	23/34			ENSP00000516346	P1
SRCAP	ENST00000483083.3	c.2968A>G	p.Ser990Gly	missense_variant	16/18	2		ENSP00000483329

Frequencies

GnomAD3 genomes AF: 0.000838 AC: 127 AN: 151514 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000972

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00171

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000707

Gnomad OTH AF: 0.00241

GnomAD3 exomes AF: 0.00115 AC: 285 AN: 248300 Hom.: 3 AF XY: 0.00123 AC XY: 166 AN XY: 134694

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.0108

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000792

Gnomad OTH exome AF: 0.00365

GnomAD4 exome AF: 0.000776 AC: 1133 AN: 1460638 Hom.: 7 Cov.: 33 AF XY: 0.000808 AC XY: 587 AN XY: 726426

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00170

Gnomad4 ASJ exome AF: 0.0111

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000507

Gnomad4 OTH exome AF: 0.00162

GnomAD4 genome AF: 0.000838 AC: 127 AN: 151632 Hom.: 0 Cov.: 32 AF XY: 0.000864 AC XY: 64 AN XY: 74092

Gnomad4 AFR AF: 0.0000969

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000707

Gnomad4 OTH AF: 0.00238

Alfa AF: 0.00130 Hom.: 4

Bravo AF: 0.000933

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00107 AC: 9

ExAC AF: 0.000694 AC: 84

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.000889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	SRCAP: BS1, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 17, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 15, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Benign	0.91
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.0025
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	D;D;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.23
Sift	Uncertain	0.012	D
Sift4G	Benign	0.36	T
Polyphen		0.0010	B
Vest4		0.37
MVP		0.20
MPC		0.16
ClinPred		0.020	T
GERP RS		5.2
Varity_R		0.17
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs150246733; hg19: chr16-30734045;