rs9878928

Variant names:

• chr3-57198476-T-C
• rs9878928
• NM_003865.3:c.374A>G
• HESX1 p.Asn125Ser

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003865.3(HESX1):​c.374A>G​(p.Asn125Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,589,044 control chromosomes in the GnomAD database, including 2,249 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N125G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.070 (1245 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (1004 hom.)
• Consequence: HESX1 NM_003865.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.44
• Publications: 16 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: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017352402).
• BP6: Variant 3-57198476-T-C is Benign according to our data. Variant chr3-57198476-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 282975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

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.374A>G	p.Asn125Ser	missense	Exon 3 of 4	NP_003856.1	Q9UBX0
	HESX1	NM_001376058.1		c.374A>G	p.Asn125Ser	missense	Exon 6 of 7	NP_001362987.1	Q9UBX0
	HESX1	NM_001376059.1		c.374A>G	p.Asn125Ser	missense	Exon 5 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.374A>G	p.Asn125Ser	missense	Exon 3 of 4	ENSP00000295934.3	Q9UBX0
	HESX1	ENST00000918124.1		c.395A>G	p.Asn132Ser	missense	Exon 3 of 4	ENSP00000588183.1
	HESX1	ENST00000647958.1		c.374A>G	p.Asn125Ser	missense	Exon 6 of 7	ENSP00000498190.1	Q9UBX0

Frequencies

GnomAD3 genomes AF: 0.0696 AC: 10584 AN: 152130 Hom.: 1240 Cov.: 32

Gnomad AFR AF: 0.240

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0289

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.0549

GnomAD2 exomes AF: 0.0179 AC: 4419 AN: 247290 AF XY: 0.0131

Gnomad AFR exome AF: 0.238

Gnomad AMR exome AF: 0.0135

Gnomad ASJ exome AF: 0.00625

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000773

Gnomad OTH exome AF: 0.00732

GnomAD4 exome AF: 0.00697 AC: 10019 AN: 1436796 Hom.: 1004 Cov.: 27 AF XY: 0.00606 AC XY: 4342 AN XY: 716234

African (AFR) AF: 0.238 AC: 7708 AN: 32362

American (AMR) AF: 0.0148 AC: 654 AN: 44110

Ashkenazi Jewish (ASJ) AF: 0.00525 AC: 136 AN: 25914

East Asian (EAS) AF: 0.00 AC: 0 AN: 39476

South Asian (SAS) AF: 0.000496 AC: 42 AN: 84750

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53328

Middle Eastern (MID) AF: 0.0138 AC: 75 AN: 5422

European-Non Finnish (NFE) AF: 0.000409 AC: 447 AN: 1091958

Other (OTH) AF: 0.0161 AC: 956 AN: 59476

GnomAD4 genome AF: 0.0698 AC: 10624 AN: 152248 Hom.: 1245 Cov.: 32 AF XY: 0.0690 AC XY: 5137 AN XY: 74450

African (AFR) AF: 0.240 AC: 9959 AN: 41508

American (AMR) AF: 0.0289 AC: 442 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00110 AC: 75 AN: 68020

Other (OTH) AF: 0.0543 AC: 115 AN: 2116

Alfa AF: 0.0234 Hom.: 1036

Bravo AF: 0.0786

Asia WGS AF: 0.0130 AC: 47 AN: 3470

EpiCase AF: 0.00147

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Combined Pituitary Hormone Deficiency, Dominant/Recessive (1)
-	-	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
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.070	N
PhyloP100		1.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.35
Sift	Benign	0.43	T
Sift4G	Benign	0.51	T
Varity_R		0.079
gMVP		0.26
Mutation Taster		=90/10	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs9878928;

hg19: chr3-57232504;