rs117480926

chr16-30729012-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.5705A>G(p.Glu1902Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0055 in 1,614,090 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1902Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0039 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (39 hom.)
• Consequence: SRCAP NM_006662.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.18

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=0.009796977).
• BP6: Variant 16-30729012-A-G is Benign according to our data. Variant chr16-30729012-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 260020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-30729012-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0039 (594/152226) while in subpopulation NFE AF= 0.00616 (419/68012). AF 95% confidence interval is 0.00567. There are 2 homozygotes in gnomad4. There are 291 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 594 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRCAP	NM_006662.3	c.5705A>G	p.Glu1902Gly	missense_variant	26/34	ENST00000262518.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRCAP	ENST00000262518.9	c.5705A>G	p.Glu1902Gly	missense_variant	26/34	2	NM_006662.3	P1
SRCAP	ENST00000411466.7	c.5705A>G	p.Glu1902Gly	missense_variant	26/34	3		P1
SRCAP	ENST00000706321.1	c.5705A>G	p.Glu1902Gly	missense_variant	26/34			P1

Frequencies

GnomAD3 genomes AF: 0.00391 AC: 594 AN: 152108 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00801

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00616

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00396 AC: 995 AN: 251408 Hom.: 5 AF XY: 0.00401 AC XY: 545 AN XY: 135880

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.00915

Gnomad NFE exome AF: 0.00592

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00567 AC: 8282 AN: 1461864 Hom.: 39 Cov.: 31 AF XY: 0.00542 AC XY: 3943 AN XY: 727230

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00122

Gnomad4 FIN exome AF: 0.00884

Gnomad4 NFE exome AF: 0.00657

Gnomad4 OTH exome AF: 0.00487

GnomAD4 genome AF: 0.00390 AC: 594 AN: 152226 Hom.: 2 Cov.: 32 AF XY: 0.00391 AC XY: 291 AN XY: 74416

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00801

Gnomad4 NFE AF: 0.00616

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00546 Hom.: 5

Bravo AF: 0.00317

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00399 AC: 484

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00540

EpiControl AF: 0.00522

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Apr 19, 2017	BS1,BS2,BP6; This alteration has an allele frequency that is greater than expected for the associated disease, was seen in a healthy adult where full penetrance of the disorder is expected at an early age, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 19, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SRCAP: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Floating-Harbor syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.10
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.21	T;T
Eigen	Benign	0.069
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.0098	T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	0.74	D;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.9	D;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.0030	D;.
Sift4G	Benign	0.10	T;T
Polyphen		0.36	B;.
Vest4		0.48
MVP		0.26
MPC		0.73
ClinPred		0.020	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.48

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: rs117480926; hg19: chr16-30740333; COSMIC: COSV99049133; COSMIC: COSV99049133;