rs149248373

chr16-30721237-C-Achr16-30721237-C-T

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.3302C>A(p.Thr1101Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00733 in 1,613,894 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. T1101M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0056 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (57 hom.)
• Consequence: SRCAP NM_006662.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.28

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=0.0060519874).
• BP6: Variant 16-30721237-C-A is Benign according to our data. Variant chr16-30721237-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 260017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-30721237-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00562 (856/152290) while in subpopulation NFE AF= 0.00866 (589/68020). AF 95% confidence interval is 0.00808. There are 5 homozygotes in gnomad4. There are 401 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 857 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRCAP	NM_006662.3	c.3302C>A	p.Thr1101Lys	missense_variant	21/34	ENST00000262518.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRCAP	ENST00000262518.9	c.3302C>A	p.Thr1101Lys	missense_variant	21/34	2	NM_006662.3	P1
SRCAP	ENST00000411466.7	c.3302C>A	p.Thr1101Lys	missense_variant	21/34	3		P1
SRCAP	ENST00000706321.1	c.3302C>A	p.Thr1101Lys	missense_variant	21/34			P1
SRCAP	ENST00000483083.3	c.2402C>A	p.Thr801Lys	missense_variant	14/18	2

Frequencies

GnomAD3 genomes AF: 0.00563 AC: 857 AN: 152172 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00667

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00556

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00867

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00554 AC: 1382 AN: 249334 Hom.: 5 AF XY: 0.00529 AC XY: 713 AN XY: 134840

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00286

Gnomad ASJ exome AF: 0.00561

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000655

Gnomad FIN exome AF: 0.00524

Gnomad NFE exome AF: 0.00919

Gnomad OTH exome AF: 0.00686

GnomAD4 exome AF: 0.00750 AC: 10967 AN: 1461604 Hom.: 57 Cov.: 33 AF XY: 0.00719 AC XY: 5231 AN XY: 727102

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00309

Gnomad4 ASJ exome AF: 0.00652

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000626

Gnomad4 FIN exome AF: 0.00669

Gnomad4 NFE exome AF: 0.00883

Gnomad4 OTH exome AF: 0.00636

GnomAD4 genome AF: 0.00562 AC: 856 AN: 152290 Hom.: 5 Cov.: 32 AF XY: 0.00539 AC XY: 401 AN XY: 74460

Gnomad4 AFR AF: 0.00144

Gnomad4 AMR AF: 0.00667

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00556

Gnomad4 NFE AF: 0.00866

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00585 Hom.: 4

Bravo AF: 0.00570

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00872 AC: 75

ExAC AF: 0.00600 AC: 729

EpiCase AF: 0.00698

EpiControl AF: 0.00800

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	SRCAP: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 26, 2017	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 31, 2016	- -

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	0.30
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
Cadd	Benign	19
Dann	Benign	0.92
DEOGEN2	Benign	0.042	T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.0061	T;T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.14	N;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.5	N;.
REVEL	Uncertain	0.34
Sift	Benign	0.039	D;.
Sift4G	Benign	0.34	T;T
Polyphen		0.48	P;.
Vest4		0.47
MVP		0.52
MPC		0.65
ClinPred		0.0072	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149248373; hg19: chr16-30732558; COSMIC: COSV99349997;