rs7536561

Positions:

• chr1-180274389-A-G
• chr1-180274389-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.52

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-AS1 (HGNC:):

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]

ACMG classification

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	UniProt
LHX4	NM_033343.4	c.983A>G	p.Asn328Ser	missense_variant	6/6	ENST00000263726.4
LHX4-AS1	NR_037642.1	n.31+262T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LHX4	ENST00000263726.4	c.983A>G	p.Asn328Ser	missense_variant	6/6	1	NM_033343.4	P1

Frequencies

GnomAD3 genomes AF: 0.420 AC: 63733 AN: 151858 Hom.: 15297 Cov.: 32

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

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.: 63 AF XY: 0.514 AC XY: 373879 AN XY: 727228

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.: 32 AF XY: 0.425 AC XY: 31560 AN XY: 74264

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Short stature-pituitary and cerebellar defects-small sella turcica syndrome Benign:3

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	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

not specified Benign:2

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Benign	0.77
DEOGEN2	Benign	0.072	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.000028	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.030	N
MutationTaster	Benign	0.00042	P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.26
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.019
MPC		0.22
ClinPred		0.0076	T
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

Other links and lift over

dbSNP: rs7536561; hg19: chr1-180243524; COSMIC: COSV55374116; COSMIC: COSV55374116;