chr3-57198465-C-T

Variant names:

• chr3-57198465-C-T
• rs143057250
• NM_003865.3:c.385G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003865.3(HESX1):​c.385G>A​(p.Val129Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000937 in 1,601,096 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (2 hom.)
• Consequence: HESX1 NM_003865.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:5
• Conservation: PhyloP100: 2.06
• Publications: 6 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029887676).
• BP6: Variant 3-57198465-C-T is Benign according to our data. Variant chr3-57198465-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 267733.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000664 (101/152186) while in subpopulation NFE AF = 0.0011 (75/68014). AF 95% confidence interval is 0.000902. There are 0 homozygotes in GnomAd4. There are 51 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.385G>A	p.Val129Ile	missense	Exon 3 of 4	NP_003856.1	Q9UBX0
	HESX1	NM_001376058.1		c.385G>A	p.Val129Ile	missense	Exon 6 of 7	NP_001362987.1	Q9UBX0
	HESX1	NM_001376059.1		c.385G>A	p.Val129Ile	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.385G>A	p.Val129Ile	missense	Exon 3 of 4	ENSP00000295934.3	Q9UBX0
	HESX1	ENST00000918124.1		c.406G>A	p.Val136Ile	missense	Exon 3 of 4	ENSP00000588183.1
	HESX1	ENST00000647958.1		c.385G>A	p.Val129Ile	missense	Exon 6 of 7	ENSP00000498190.1	Q9UBX0

Frequencies

GnomAD3 genomes AF: 0.000664 AC: 101 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000810 AC: 202 AN: 249392 AF XY: 0.000815

Gnomad AFR exome AF: 0.000252

Gnomad AMR exome AF: 0.000583

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.000966 AC: 1400 AN: 1448910 Hom.: 2 Cov.: 28 AF XY: 0.000909 AC XY: 656 AN XY: 721554

African (AFR) AF: 0.000242 AC: 8 AN: 33014

American (AMR) AF: 0.000517 AC: 23 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.00223 AC: 58 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.000199 AC: 17 AN: 85398

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53346

Middle Eastern (MID) AF: 0.000722 AC: 4 AN: 5544

European-Non Finnish (NFE) AF: 0.00112 AC: 1234 AN: 1101602

Other (OTH) AF: 0.000885 AC: 53 AN: 59920

GnomAD4 genome AF: 0.000664 AC: 101 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000686 AC XY: 51 AN XY: 74382

African (AFR) AF: 0.000169 AC: 7 AN: 41518

American (AMR) AF: 0.000392 AC: 6 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00110 AC: 75 AN: 68014

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00110 Hom.: 0

Bravo AF: 0.000786

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00187 AC: 16

ExAC AF: 0.000791 AC: 96

Asia WGS AF: 0.000289 AC: 1 AN: 3470

EpiCase AF: 0.00131

EpiControl AF: 0.00142

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	3	1	Septo-optic dysplasia sequence (4)
-	1	-	Amenorrhea (1)
-	-	1	HESX1-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	not specified (1)
-	1	-	Pituitary hormone deficiency, combined, 1 (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	0.088
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	0.15
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.030	T
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	0.075	N
PhyloP100		2.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.73	N
REVEL	Uncertain	0.49
Sift	Benign	0.070	T
Sift4G	Benign	0.11	T
Polyphen		0.92	P
Vest4		0.15
MVP		0.91
MPC		0.074
ClinPred		0.031	T
GERP RS		3.8
Varity_R		0.10
gMVP		0.38
Mutation Taster		=72/28	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: rs143057250; hg19: chr3-57232493;