14-21352719-C-T

Position:

• chr14-21352719-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_007192.4(SUPT16H):​c.3098G>A​(p.Arg1033His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,614,074 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (8 hom.)
• Consequence: SUPT16H NM_007192.4 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.95

Genes affected

SUPT16H (HGNC:11465): (SPT16 homolog, facilitates chromatin remodeling subunit) Transcription of protein-coding genes can be reconstituted on naked DNA with only the general transcription factors and RNA polymerase II. However, this minimal system cannot transcribe DNA packaged into chromatin, indicating that accessory factors may facilitate access to DNA. One such factor, FACT (facilitates chromatin transcription), interacts specifically with histones H2A/H2B to effect nucleosome disassembly and transcription elongation. FACT is composed of an 80 kDa subunit and a 140 kDa subunit; this gene encodes the 140 kDa subunit. [provided by RefSeq, Feb 2009]

SUPT16H (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SUPT16H. . Gene score misZ 5.1004 (greater than the threshold 3.09). Trascript score misZ 7.0133 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder, neurodevelopmental disorder with dysmorphic facies and thin corpus callosum.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0074258745).
• BP6: Variant 14-21352719-C-T is Benign according to our data. Variant chr14-21352719-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3039102.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 201 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SUPT16H	NM_007192.4	c.3098G>A	p.Arg1033His	missense_variant	26/26	ENST00000216297.7	NP_009123.1
SUPT16H	XM_047430899.1	c.2903G>A	p.Arg968His	missense_variant	25/25		XP_047286855.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SUPT16H	ENST00000216297.7	c.3098G>A	p.Arg1033His	missense_variant	26/26	1	NM_007192.4	ENSP00000216297.2
SUPT16H	ENST00000557394.5	n.1084G>A		non_coding_transcript_exon_variant	6/6	2

Frequencies

GnomAD3 genomes AF: 0.00132 AC: 201 AN: 152074 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00262

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00128 AC: 321 AN: 250092 Hom.: 1 AF XY: 0.00126 AC XY: 171 AN XY: 135320

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00220

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00219 AC: 3205 AN: 1461882 Hom.: 8 Cov.: 31 AF XY: 0.00216 AC XY: 1572 AN XY: 727244

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000962

Gnomad4 FIN exome AF: 0.000374

Gnomad4 NFE exome AF: 0.00266

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.00132 AC: 201 AN: 152192 Hom.: 1 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74398

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00146

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00262

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00191 Hom.: 1

Bravo AF: 0.00137

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00105 AC: 128

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00184

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

SUPT16H-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 15, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.041
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.047
Sift	Benign	0.12	T
Sift4G	Benign	0.069	T
Polyphen		0.0020	B
Vest4		0.31
MVP		0.10
MPC		0.67
ClinPred		0.026	T
GERP RS		5.0
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Varity_R		0.065
gMVP		0.15

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: rs150316403; hg19: chr14-21820878;