3-121631940-G-C

Position:

• chr3-121631940-G-C

Variant summary

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

The NM_005335.6(HCLS1):​c.1367C>G​(p.Thr456Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HCLS1 NM_005335.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.87

Genes affected

HCLS1 (HGNC:4844): (hematopoietic cell-specific Lyn substrate 1) Enables RNA polymerase II-specific DNA-binding transcription factor binding activity and protein kinase binding activity. Involved in several processes, including positive regulation of intracellular signal transduction; positive regulation of protein phosphorylation; and regulation of transcription, DNA-templated. Located in cytosol; nucleus; and plasma membrane. Part of transcription regulator complex. [provided by Alliance of Genome Resources, Apr 2022]

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/exons	MANE	UniProt
HCLS1	NM_005335.6	c.1367C>G	p.Thr456Ser	missense_variant	14/14	ENST00000314583.8
HCLS1	NM_001292041.2	c.1256C>G	p.Thr419Ser	missense_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCLS1	ENST00000314583.8	c.1367C>G	p.Thr456Ser	missense_variant	14/14	1	NM_005335.6	P1
HCLS1	ENST00000428394.6	c.1256C>G	p.Thr419Ser	missense_variant	13/13	2
HCLS1	ENST00000473883.5	n.2170C>G		non_coding_transcript_exon_variant	9/9	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2023

The c.1367C>G (p.T456S) alteration is located in exon 14 (coding exon 13) of the HCLS1 gene. This alteration results from a C to G substitution at nucleotide position 1367, causing the threonine (T) at amino acid position 456 to be replaced by a serine (S). 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	Benign	0.20
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T;T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Uncertain	0.31
Sift	Benign	0.041	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;D
Vest4		0.17
MutPred		0.52		Gain of glycosylation at T456 (P = 0.0421);.;
MVP		0.75
MPC		0.32
ClinPred		0.94	D
GERP RS		5.5
Varity_R		0.54
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-121350787;