chr3-57198302-T-C

Variant names:

• chr3-57198302-T-C
• rs1579346889
• NM_003865.3:c.460-7A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP3 BP6_Moderate

The NM_003865.3(HESX1):​c.460-7A>G variant causes a splice region, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HESX1 NM_003865.3 splice_region, intron
• Scores: Splicing: ADA: 0.9984
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.72
• Publications: 0 publications found

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]

HESX1 Gene-Disease associations (from GenCC):

• septooptic dysplasia

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• combined pituitary hormone deficiencies, genetic form

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypothyroidism due to deficient transcription factors involved in pituitary development or function

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pituitary stalk interruption syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 3-57198302-T-C is Benign according to our data. Variant chr3-57198302-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 801979.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003865.3. 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
	HESX1	NM_003865.3	MANE Select	c.460-7A>G		splice_region intron	N/A	NP_003856.1	Q9UBX0
	HESX1	NM_001376058.1		c.460-7A>G		splice_region intron	N/A	NP_001362987.1	Q9UBX0
	HESX1	NM_001376059.1		c.460-7A>G		splice_region intron	N/A	NP_001362988.1	Q9UBX0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HESX1	ENST00000295934.8	TSL:1 MANE Select	c.460-7A>G		splice_region intron	N/A	ENSP00000295934.3	Q9UBX0
	HESX1	ENST00000918124.1		c.481-7A>G		splice_region intron	N/A	ENSP00000588183.1
	HESX1	ENST00000647958.1		c.460-7A>G		splice_region intron	N/A	ENSP00000498190.1	Q9UBX0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Septo-optic dysplasia sequence (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	26
DANN	Benign	0.79
PhyloP100		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.87		Position offset: -1
DS_AL_spliceai		0.75		Position offset: -7

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

Other links and lift over

dbSNP: rs1579346889; hg19: chr3-57232330;