16-30722251-G-T

Variant names:

• chr16-30722251-G-T
• rs201658767
• NM_006662.3:c.3671G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006662.3(SRCAP):​c.3671G>T​(p.Arg1224Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1224H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SRCAP NM_006662.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.16
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

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

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.3671G>T	p.Arg1224Leu	missense	Exon 22 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.3671G>T	p.Arg1224Leu	missense	Exon 22 of 34	ENSP00000262518.4	Q6ZRS2-1
	ENSG00000282034	ENST00000380361.7	TSL:2	n.3326G>T		non_coding_transcript_exon	Exon 18 of 31	ENSP00000369719.3	A0A0C4DFX4
	SRCAP	ENST00000411466.7	TSL:3	c.3671G>T	p.Arg1224Leu	missense	Exon 22 of 34	ENSP00000405186.3	C9J4U4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.064	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	1.1	L
PhyloP100		5.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.57
MutPred		0.47		Loss of MoRF binding (P = 0.0186)
MVP		0.42
MPC		0.89
ClinPred		0.88	D
GERP RS		4.7
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.23
gMVP		0.43
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs201658767; hg19: chr16-30733572;