rs7536561

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_033343.4(LHX4):c.983A>G(p.Asn328Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 1,613,834 control chromosomes in the GnomAD database, including 209,181 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.42 ( 15289 hom., cov: 32)

Exomes 𝑓: 0.51 ( 193892 hom. )

Consequence

LHX4
NM_033343.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.52

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 links:

ACBD6 (HGNC:23339): (acyl-CoA binding domain containing 6) Predicted to enable fatty-acyl-CoA binding activity and lipid binding activity. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACBD6 links:

ACBD6 (HGNC:):

ACBD6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.7808957E-5).

BP6

Variant 1-180274389-A-G is Benign according to our data. Variant chr1-180274389-A-G is described in ClinVar as [Benign]. Clinvar id is 262225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-180274389-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LHX4	NM_033343.4 linkuse as main transcript	c.983A>G	p.Asn328Ser	missense_variant	6/6	ENST00000263726.4	NP_203129.1	Q969G2A0A0S2Z5S4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LHX4	ENST00000263726.4 linkuse as main transcript	c.983A>G	p.Asn328Ser	missense_variant	6/6	1	NM_033343.4	ENSP00000263726.2		Q969G2

Frequencies

GnomAD3 genomes

AF:

0.420

AC:

63733

AN:

151858

Hom.:

15297

Cov.:

show subpopulations

Gnomad AFR

AF:

0.188

Gnomad AMI

AF:

0.580

Gnomad AMR

AF:

0.345

Gnomad ASJ

AF:

0.520

Gnomad EAS

AF:

0.593

Gnomad SAS

AF:

0.608

Gnomad FIN

AF:

0.577

Gnomad MID

AF:

0.548

Gnomad NFE

AF:

0.518

Gnomad OTH

AF:

0.431

GnomAD3 exomes

AF:

0.482

AC:

121287

AN:

251416

Hom.:

31656

AF XY:

0.502

AC XY:

68274

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.183

Gnomad AMR exome

AF:

0.257

Gnomad ASJ exome

AF:

0.521

Gnomad EAS exome

AF:

0.589

Gnomad SAS exome

AF:

0.601

Gnomad FIN exome

AF:

0.577

Gnomad NFE exome

AF:

0.523

Gnomad OTH exome

AF:

0.493

GnomAD4 exome

AF:

0.509

AC:

744210

AN:

1461858

Hom.:

193892

Cov.:

AF XY:

0.514

AC XY:

373879

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.176

Gnomad4 AMR exome

AF:

0.269

Gnomad4 ASJ exome

AF:

0.523

Gnomad4 EAS exome

AF:

0.581

Gnomad4 SAS exome

AF:

0.601

Gnomad4 FIN exome

AF:

0.572

Gnomad4 NFE exome

AF:

0.516

Gnomad4 OTH exome

AF:

0.498

GnomAD4 genome

AF:

0.419

AC:

63710

AN:

151976

Hom.:

15289

Cov.:

AF XY:

0.425

AC XY:

31560

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.188

Gnomad4 AMR

AF:

0.344

Gnomad4 ASJ

AF:

0.520

Gnomad4 EAS

AF:

0.593

Gnomad4 SAS

AF:

0.607

Gnomad4 FIN

AF:

0.577

Gnomad4 NFE

AF:

0.518

Gnomad4 OTH

AF:

0.426

Alfa

AF:

0.503

Hom.:

49653

Bravo

AF:

0.390

TwinsUK

AF:

0.525

AC:

1948

ALSPAC

AF:

0.517

AC:

1992

ESP6500AA

AF:

0.205

AC:

903

ESP6500EA

AF:

0.516

AC:

4438

ExAC

AF:

0.485

AC:

58862

Asia WGS

AF:

0.510

AC:

1771

AN:

3478

EpiCase

AF:

0.534

EpiControl

AF:

0.532

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Short stature-pituitary and cerebellar defects-small sella turcica syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.072

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.59

MetaRNN

Benign

0.000028

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.030

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.060

REVEL

Benign

0.26

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.019

MPC

0.22

ClinPred

0.0076

GERP RS

3.3

Varity_R

0.047

gMVP

0.19

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over