3-57198204-A-G

Variant names:

• chr3-57198204-A-G
• NM_003865.3:c.551T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003865.3(HESX1):​c.551T>C​(p.Leu184Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HESX1 NM_003865.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.41

Genes affected

HESX1 (HGNC:4877): (HESX homeobox 1) This gene encodes a conserved homeobox protein that is a transcriptional repressor in the developing forebrain and pituitary gland. Mutations in this gene are associated with septooptic dysplasia, HESX1-related growth hormone deficiency, and combined pituitary hormone deficiency. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26178837).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HESX1	NM_003865.3	c.551T>C	p.Leu184Pro	missense_variant	Exon 4 of 4	ENST00000295934.8	NP_003856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HESX1	ENST00000295934.8	c.551T>C	p.Leu184Pro	missense_variant	Exon 4 of 4	1	NM_003865.3	ENSP00000295934.3
HESX1	ENST00000647958.1	c.551T>C	p.Leu184Pro	missense_variant	Exon 7 of 7			ENSP00000498190.1
HESX1	ENST00000473921.2	c.449T>C	p.Leu150Pro	missense_variant	Exon 3 of 3	5		ENSP00000418918.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.551T>C (p.L184P) alteration is located in exon 4 (coding exon 4) of the HESX1 gene. This alteration results from a T to C substitution at nucleotide position 551, causing the leucine (L) at amino acid position 184 to be replaced by a proline (P). 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	0.11
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.49	.;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	0.90	L;L;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.30	.;N;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.014	.;D;D
Sift4G	Benign	0.070	.;T;T
Polyphen		0.028	B;B;.
Vest4		0.27, 0.25
MutPred		0.30		Gain of relative solvent accessibility (P = 0.0098);Gain of relative solvent accessibility (P = 0.0098);.;
MVP		0.95
MPC		0.31
ClinPred		0.82	D
GERP RS		4.3
Varity_R		0.18
gMVP		0.59

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-57232232;