rs587784443

Positions:

• chr16-30724727-T-A
• chr16-30724727-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_006662.3(SRCAP):​c.5303T>A​(p.Leu1768Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SRCAP NM_006662.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SRCAP	NM_006662.3	c.5303T>A	p.Leu1768Gln	missense_variant	25/34	ENST00000262518.9	NP_006653.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SRCAP	ENST00000262518.9	c.5303T>A	p.Leu1768Gln	missense_variant	25/34	2	NM_006662.3	ENSP00000262518	P1
SRCAP	ENST00000411466.7	c.5303T>A	p.Leu1768Gln	missense_variant	25/34	3		ENSP00000405186	P1
SRCAP	ENST00000706321.1	c.5303T>A	p.Leu1768Gln	missense_variant	25/34			ENSP00000516346	P1
SRCAP	ENST00000483083.3	c.4403T>A	p.Leu1468Gln	missense_variant	18/18	2		ENSP00000483329

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249696 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135080

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	23
DANN	Benign	0.93
DEOGEN2	Benign	0.046	T;T
Eigen	Benign	0.092
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.85	D;T
M_CAP	Uncertain	0.093	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	0.80	N;N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.7	N;.
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	0.29	T;T
Polyphen		0.79	P;.
Vest4		0.74
MutPred		0.14		Loss of sheet (P = 0.0457);.;
MVP		0.87
MPC		0.72
ClinPred		0.40	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.33
gMVP		0.47

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: rs587784443; hg19: chr16-30736048;