chr1-180266593-C-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_033343.4(LHX4):​c.450C>T​(p.Asn150Asn) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,613,830 control chromosomes in the GnomAD database, including 551 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 265 hom., cov: 32)
Exomes 𝑓: 0.014 ( 286 hom. )

Consequence

LHX4
NM_033343.4 splice_region, synonymous

Scores

2
Splicing: ADA: 0.0004384
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.769

Publications

12 publications found
Variant links:
Genes affected
LHX4 (HGNC:21734): (LIM homeobox 4) This gene encodes a member of a large protein family which contains the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein is a transcription factor involved in the control of differentiation and development of the pituitary gland. Mutations in this gene cause combined pituitary hormone deficiency 4. [provided by RefSeq, Dec 2010]
LHX4 Gene-Disease associations (from GenCC):
  • short stature-pituitary and cerebellar defects-small sella turcica syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
  • 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
  • pituitary stalk interruption syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.53).
BP6
Variant 1-180266593-C-T is Benign according to our data. Variant chr1-180266593-C-T is described in ClinVar as [Benign]. Clinvar id is 262223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.769 with no splicing effect.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
LHX4NM_033343.4 linkc.450C>T p.Asn150Asn splice_region_variant, synonymous_variant Exon 3 of 6 ENST00000263726.4 NP_203129.1 Q969G2A0A0S2Z5S4
LHX4XM_011510105.3 linkc.267C>T p.Asn89Asn splice_region_variant, synonymous_variant Exon 3 of 6 XP_011508407.1
LHX4XM_011510106.4 linkc.267C>T p.Asn89Asn splice_region_variant, synonymous_variant Exon 3 of 6 XP_011508408.1
LHX4XM_011510108.3 linkc.225C>T p.Asn75Asn splice_region_variant, synonymous_variant Exon 3 of 6 XP_011508410.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
LHX4ENST00000263726.4 linkc.450C>T p.Asn150Asn splice_region_variant, synonymous_variant Exon 3 of 6 1 NM_033343.4 ENSP00000263726.2 Q969G2
LHX4ENST00000561113.1 linkn.386C>T splice_region_variant, non_coding_transcript_exon_variant Exon 2 of 4 2 ENSP00000452783.1 H0YKF4

Frequencies

GnomAD3 genomes
AF:
0.0389
AC:
5918
AN:
152112
Hom.:
261
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.103
Gnomad AMI
AF:
0.0175
Gnomad AMR
AF:
0.0183
Gnomad ASJ
AF:
0.0179
Gnomad EAS
AF:
0.0146
Gnomad SAS
AF:
0.0178
Gnomad FIN
AF:
0.0272
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.0112
Gnomad OTH
AF:
0.0359
GnomAD2 exomes
AF:
0.0190
AC:
4763
AN:
250414
AF XY:
0.0173
show subpopulations
Gnomad AFR exome
AF:
0.105
Gnomad AMR exome
AF:
0.00918
Gnomad ASJ exome
AF:
0.0148
Gnomad EAS exome
AF:
0.0111
Gnomad FIN exome
AF:
0.0271
Gnomad NFE exome
AF:
0.0105
Gnomad OTH exome
AF:
0.0160
GnomAD4 exome
AF:
0.0139
AC:
20282
AN:
1461602
Hom.:
286
Cov.:
32
AF XY:
0.0136
AC XY:
9878
AN XY:
727088
show subpopulations
African (AFR)
AF:
0.101
AC:
3378
AN:
33472
American (AMR)
AF:
0.0102
AC:
455
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
0.0150
AC:
392
AN:
26130
East Asian (EAS)
AF:
0.0193
AC:
767
AN:
39688
South Asian (SAS)
AF:
0.0172
AC:
1487
AN:
86222
European-Finnish (FIN)
AF:
0.0243
AC:
1298
AN:
53400
Middle Eastern (MID)
AF:
0.0210
AC:
121
AN:
5768
European-Non Finnish (NFE)
AF:
0.0101
AC:
11282
AN:
1111822
Other (OTH)
AF:
0.0182
AC:
1102
AN:
60384
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.473
Heterozygous variant carriers
0
1035
2070
3105
4140
5175
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
502
1004
1506
2008
2510
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0391
AC:
5946
AN:
152228
Hom.:
265
Cov.:
32
AF XY:
0.0382
AC XY:
2844
AN XY:
74438
show subpopulations
African (AFR)
AF:
0.104
AC:
4298
AN:
41508
American (AMR)
AF:
0.0182
AC:
279
AN:
15304
Ashkenazi Jewish (ASJ)
AF:
0.0179
AC:
62
AN:
3472
East Asian (EAS)
AF:
0.0145
AC:
75
AN:
5178
South Asian (SAS)
AF:
0.0178
AC:
86
AN:
4826
European-Finnish (FIN)
AF:
0.0272
AC:
289
AN:
10620
Middle Eastern (MID)
AF:
0.00680
AC:
2
AN:
294
European-Non Finnish (NFE)
AF:
0.0112
AC:
762
AN:
68000
Other (OTH)
AF:
0.0364
AC:
77
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.505
Heterozygous variant carriers
0
269
539
808
1078
1347
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
60
120
180
240
300
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0193
Hom.:
312
Bravo
AF:
0.0402
Asia WGS
AF:
0.0350
AC:
123
AN:
3478
EpiCase
AF:
0.0122
EpiControl
AF:
0.0112

ClinVar

Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:4
-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Jun 10, 2021
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 28, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:3
-
Clinical Genetics, Academic Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 21, 2017
Eurofins Ntd Llc (ga)
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Short stature-pituitary and cerebellar defects-small sella turcica syndrome Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.53
CADD
Benign
9.0
DANN
Benign
0.88
PhyloP100
-0.77
Mutation Taster
=74/26
polymorphism (auto)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00044
dbscSNV1_RF
Benign
0.054
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

Other links and lift over

dbSNP: rs16855642; hg19: chr1-180235728; COSMIC: COSV107227508; COSMIC: COSV107227508; API