rs139339184

Positions:

• chr16-30711901-G-A

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.1559G>A​(p.Ser520Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000889 in 1,613,902 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00094 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (7 hom.)
• Consequence: SRCAP NM_006662.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.55

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 where missense usually causes diseases, SRCAP
• BP4: Computational evidence support a benign effect (MetaRNN=0.007154882).
• BP6: Variant 16-30711901-G-A is Benign according to our data. Variant chr16-30711901-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 218688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-30711901-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000884 (1292/1461766) while in subpopulation MID AF= 0.0146 (84/5768). AF 95% confidence interval is 0.0121. There are 7 homozygotes in gnomad4_exome. There are 676 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 143 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRCAP	NM_006662.3	c.1559G>A	p.Ser520Asn	missense_variant	12/34	ENST00000262518.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRCAP	ENST00000262518.9	c.1559G>A	p.Ser520Asn	missense_variant	12/34	2	NM_006662.3	P1
SRCAP	ENST00000411466.7	c.1559G>A	p.Ser520Asn	missense_variant	12/34	3		P1
SRCAP	ENST00000706321.1	c.1559G>A	p.Ser520Asn	missense_variant	12/34			P1
SRCAP	ENST00000483083.3	c.659G>A	p.Ser220Asn	missense_variant	5/18	2

Frequencies

GnomAD3 genomes AF: 0.000941 AC: 143 AN: 152018 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00171

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00125 AC: 314 AN: 251278 Hom.: 3 AF XY: 0.00135 AC XY: 183 AN XY: 135802

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000976

Gnomad OTH exome AF: 0.00407

GnomAD4 exome AF: 0.000884 AC: 1292 AN: 1461766 Hom.: 7 Cov.: 32 AF XY: 0.000930 AC XY: 676 AN XY: 727164

Gnomad4 AFR exome AF: 0.000806

Gnomad4 AMR exome AF: 0.00170

Gnomad4 ASJ exome AF: 0.0112

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000618

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.000940 AC: 143 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.000955 AC XY: 71 AN XY: 74380

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000941

Gnomad4 OTH AF: 0.00238

Alfa AF: 0.00160 Hom.: 6

Bravo AF: 0.00104

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000807 AC: 98

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 10, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	SRCAP: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 01, 2024	- -

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	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 10, 2022

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Benign	0.83
DEOGEN2	Benign	0.037	T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.046
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.0072	T;T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	0.66	D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.81	N;.
REVEL	Benign	0.24
Sift	Uncertain	0.020	D;.
Sift4G	Benign	0.22	T;T
Polyphen		0.0010	B;.
Vest4		0.19
MVP		0.26
MPC		0.50
ClinPred		0.0081	T
GERP RS		3.9
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.082
gMVP		0.12

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: rs139339184; hg19: chr16-30723222;