1-180274389-A-G

Variant names:

• chr1-180274389-A-G
• rs7536561
• NM_033343.4:c.983A>G

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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:7
• Conservation: PhyloP100: 2.52
• Publications: 46 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]

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]

LHX4-AS1 (HGNC:40982): (LHX4 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 262225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033343.4. 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
	LHX4	NM_033343.4	MANE Select	c.983A>G	p.Asn328Ser	missense	Exon 6 of 6	NP_203129.1	A0A0S2Z5S4
	LHX4-AS1	NR_037642.1		n.31+262T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHX4	ENST00000263726.4	TSL:1 MANE Select	c.983A>G	p.Asn328Ser	missense	Exon 6 of 6	ENSP00000263726.2	Q969G2
	LHX4	ENST00000930099.1		c.968A>G	p.Asn323Ser	missense	Exon 6 of 6	ENSP00000600158.1
	ACBD6	ENST00000642319.1		c.*936+262T>C		intron	N/A	ENSP00000495710.1	Q9BR61

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

GnomAD2 exomes AF: 0.482 AC: 121287 AN: 251416 AF XY: 0.502

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 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

African (AFR) AF: 0.176 AC: 5885 AN: 33480

American (AMR) AF: 0.269 AC: 12047 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.523 AC: 13663 AN: 26136

East Asian (EAS) AF: 0.581 AC: 23053 AN: 39700

South Asian (SAS) AF: 0.601 AC: 51822 AN: 86258

European-Finnish (FIN) AF: 0.572 AC: 30557 AN: 53418

Middle Eastern (MID) AF: 0.546 AC: 3148 AN: 5768

European-Non Finnish (NFE) AF: 0.516 AC: 573956 AN: 1111978

Other (OTH) AF: 0.498 AC: 30079 AN: 60396

GnomAD4 genome AF: 0.419 AC: 63710 AN: 151976 Hom.: 15289 Cov.: 32 AF XY: 0.425 AC XY: 31560 AN XY: 74264

African (AFR) AF: 0.188 AC: 7783 AN: 41476

American (AMR) AF: 0.344 AC: 5258 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.520 AC: 1803 AN: 3468

East Asian (EAS) AF: 0.593 AC: 3039 AN: 5122

South Asian (SAS) AF: 0.607 AC: 2926 AN: 4818

European-Finnish (FIN) AF: 0.577 AC: 6097 AN: 10564

Middle Eastern (MID) AF: 0.531 AC: 155 AN: 292

European-Non Finnish (NFE) AF: 0.518 AC: 35222 AN: 67938

Other (OTH) AF: 0.426 AC: 898 AN: 2110

Alfa AF: 0.490 Hom.: 86089

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Short stature-pituitary and cerebellar defects-small sella turcica syndrome (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.5
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
Mutation Taster		=94/6	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: rs7536561; hg19: chr1-180243524; COSMIC: COSV55374116; COSMIC: COSV55374116;