17-58346292-C-A

Variant names:

• chr17-58346292-C-A
• rs1972284766
• NM_003168.3:c.308G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003168.3(SUPT4H1):​c.308G>T​(p.Ser103Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SUPT4H1 NM_003168.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.26

Genes affected

SUPT4H1 (HGNC:11467): (SPT4 homolog, DSIF elongation factor subunit) This gene encodes the small subunit of DRB (5,6-dichloro-1-beta-d-ribofuranosylbenzimidazole) sensitivity-inducing factor (DSIF) complex, which regulates mRNA processing and transcription elongation by RNA polymerase II. The encoded protein is localized to the nucleus and interacts with the large subunit (SUPT5H) to form the DSIF complex. Related pseudogenes have been identified on chromosomes 2 and 12. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2012]

ENSG00000285897 (HGNC:):

TSPOAP1-AS1 (HGNC:44148): (TSPOAP1, SUPT4H1 and RNF43 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUPT4H1	NM_003168.3	c.308G>T	p.Ser103Ile	missense_variant	Exon 5 of 5	ENST00000225504.8	NP_003159.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUPT4H1	ENST00000225504.8	c.308G>T	p.Ser103Ile	missense_variant	Exon 5 of 5	1	NM_003168.3	ENSP00000225504.3
ENSG00000285897	ENST00000648873.1	n.*399G>T		non_coding_transcript_exon_variant	Exon 13 of 13			ENSP00000497686.1
ENSG00000285897	ENST00000648873.1	n.*399G>T		3_prime_UTR_variant	Exon 13 of 13			ENSP00000497686.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461838 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727222

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.308G>T (p.S103I) alteration is located in exon 5 (coding exon 5) of the SUPT4H1 gene. This alteration results from a G to T substitution at nucleotide position 308, causing the serine (S) at amino acid position 103 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T;.;.;T
Eigen	Benign	0.095
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	.;D;D;D
M_CAP	Benign	0.0062	T
MetaRNN	Uncertain	0.45	T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.5	L;.;.;L
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.7	D;.;.;.
REVEL	Uncertain	0.33
Sift	Benign	0.060	T;.;.;.
Sift4G	Benign	0.12	T;T;T;T
Polyphen		0.019	B;.;.;B
Vest4		0.66
MutPred		0.47		Loss of disorder (P = 0.011);.;.;Loss of disorder (P = 0.011);
MVP		0.34
MPC		0.89
ClinPred		0.97	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.56

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: rs1972284766; hg19: chr17-56423653;