chr3-57198230-C-T

Variant names:

• chr3-57198230-C-T
• rs141063672
• NM_003865.3:c.525G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_003865.3(HESX1):​c.525G>A​(p.Ala175Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,611,574 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (2 hom.)
• Consequence: HESX1 NM_003865.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: -1.93
• Publications: 2 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 3-57198230-C-T is Benign according to our data. Variant chr3-57198230-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197222.
• BP7: Synonymous conserved (PhyloP=-1.93 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00118 (180/152026) while in subpopulation NFE AF = 0.00212 (144/67958). AF 95% confidence interval is 0.00184. There are 0 homozygotes in GnomAd4. There are 73 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

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.525G>A	p.Ala175Ala	synonymous	Exon 4 of 4	NP_003856.1	Q9UBX0
	HESX1	NM_001376058.1		c.525G>A	p.Ala175Ala	synonymous	Exon 7 of 7	NP_001362987.1	Q9UBX0
	HESX1	NM_001376059.1		c.525G>A	p.Ala175Ala	synonymous	Exon 6 of 6	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.525G>A	p.Ala175Ala	synonymous	Exon 4 of 4	ENSP00000295934.3	Q9UBX0
	HESX1	ENST00000918124.1		c.546G>A	p.Ala182Ala	synonymous	Exon 4 of 4	ENSP00000588183.1
	HESX1	ENST00000647958.1		c.525G>A	p.Ala175Ala	synonymous	Exon 7 of 7	ENSP00000498190.1	Q9UBX0

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 180 AN: 151908 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000951

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000993 AC: 249 AN: 250672 AF XY: 0.00108

Gnomad AFR exome AF: 0.000371

Gnomad AMR exome AF: 0.000522

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00182

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00178 AC: 2598 AN: 1459548 Hom.: 2 Cov.: 30 AF XY: 0.00179 AC XY: 1300 AN XY: 726088

African (AFR) AF: 0.000359 AC: 12 AN: 33392

American (AMR) AF: 0.000470 AC: 21 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39540

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86044

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00222 AC: 2468 AN: 1110400

Other (OTH) AF: 0.00116 AC: 70 AN: 60276

GnomAD4 genome AF: 0.00118 AC: 180 AN: 152026 Hom.: 0 Cov.: 32 AF XY: 0.000982 AC XY: 73 AN XY: 74318

African (AFR) AF: 0.000434 AC: 18 AN: 41490

American (AMR) AF: 0.000982 AC: 15 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.0000951 AC: 1 AN: 10518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00212 AC: 144 AN: 67958

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00160 Hom.: 0

Bravo AF: 0.00120

EpiCase AF: 0.00224

EpiControl AF: 0.00202

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	3	not specified (3)
-	1	-	Septo-optic dysplasia sequence (1)
-	-	1	Septo-optic dysplasia sequence;C2750027:GROWTH HORMONE DEFICIENCY WITH PITUITARY ANOMALIES (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	5.0
DANN	Benign	0.56
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs141063672; hg19: chr3-57232258;