rs6661125

Variant names:

• chr1-180257765-A-G
• rs6661125
• NM_033343.4:c.249-8627A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-180257765-A-G
• chr1-180257765-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033343.4(LHX4):​c.249-8627A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 152,160 control chromosomes in the GnomAD database, including 6,378 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.25 (6378 hom., cov: 33)
• Consequence: LHX4 NM_033343.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.201
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHX4	NM_033343.4	c.249-8627A>G		intron_variant	Intron 2 of 5	ENST00000263726.4	NP_203129.1
LHX4	XM_011510105.3	c.66-8627A>G		intron_variant	Intron 2 of 5		XP_011508407.1
LHX4	XM_011510106.4	c.66-8627A>G		intron_variant	Intron 2 of 5		XP_011508408.1
LHX4	XM_011510108.3	c.-28-8438A>G		intron_variant	Intron 1 of 5		XP_011508410.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHX4	ENST00000263726.4	c.249-8627A>G		intron_variant	Intron 2 of 5	1	NM_033343.4	ENSP00000263726.2
LHX4	ENST00000561113.1	n.185-8627A>G		intron_variant	Intron 1 of 3	2		ENSP00000452783.1

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37795 AN: 152042 Hom.: 6355 Cov.: 33

Gnomad AFR AF: 0.476

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.0243

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.172

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.221

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.249 AC: 37868 AN: 152160 Hom.: 6378 Cov.: 33 AF XY: 0.244 AC XY: 18166 AN XY: 74410

African (AFR) AF: 0.477 AC: 19763 AN: 41470

American (AMR) AF: 0.152 AC: 2318 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 685 AN: 3468

East Asian (EAS) AF: 0.0241 AC: 125 AN: 5182

South Asian (SAS) AF: 0.160 AC: 770 AN: 4826

European-Finnish (FIN) AF: 0.190 AC: 2017 AN: 10594

Middle Eastern (MID) AF: 0.178 AC: 52 AN: 292

European-Non Finnish (NFE) AF: 0.168 AC: 11418 AN: 68008

Other (OTH) AF: 0.224 AC: 474 AN: 2114

Alfa AF: 0.179 Hom.: 4931

Bravo AF: 0.253

Asia WGS AF: 0.123 AC: 429 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.5
DANN	Benign	0.61
PhyloP100		-0.20
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs6661125; hg19: chr1-180226900;