rs199469464

Variant names:

• chr16-30737370-C-T
• rs199469464
• NM_006662.3:c.7330C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_006662.3(SRCAP):​c.7330C>T​(p.Arg2444*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SRCAP NM_006662.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:29 O:1
• Conservation: PhyloP100: 4.82
• Publications: 25 publications found

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]

SRCAP Gene-Disease associations (from GenCC):

• developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Floating-Harbor syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000282034 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 37 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-30737370-C-T is Pathogenic according to our data. Variant chr16-30737370-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 30908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006662.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRCAP	NM_006662.3	MANE Select	c.7330C>T	p.Arg2444*	stop_gained	Exon 34 of 34	NP_006653.2	Q6ZRS2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRCAP	ENST00000262518.9	TSL:2 MANE Select	c.7330C>T	p.Arg2444*	stop_gained	Exon 34 of 34	ENSP00000262518.4	Q6ZRS2-1
	ENSG00000282034	ENST00000380361.7	TSL:2	n.6799C>T		non_coding_transcript_exon	Exon 29 of 31	ENSP00000369719.3	A0A0C4DFX4
	SRCAP	ENST00000411466.7	TSL:3	c.7330C>T	p.Arg2444*	stop_gained	Exon 34 of 34	ENSP00000405186.3	C9J4U4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461458 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727038

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111872

Other (OTH) AF: 0.00 AC: 0 AN: 60372

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
13	-	-	Floating-Harbor syndrome (14)
9	-	-	not provided (9)
1	-	-	Developmental delay (1)
1	-	-	Developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Monogenic short statue (1)
1	-	-	Neurodevelopmental delay (1)
1	-	-	See cases (1)
1	-	-	SRCAP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		4.8
Vest4		0.69
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199469464; hg19: chr16-30748691; COSMIC: COSV52667926; COSMIC: COSV52667926;