chr1-180230592-T-C

Variant names:

• chr1-180230592-T-C
• rs75857235
• NM_033343.4:c.63T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_033343.4(LHX4):​c.63T>C​(p.Gly21Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00478 in 1,613,584 control chromosomes in the GnomAD database, including 382 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (48 hom., cov: 31)
  • Exomes 𝑓: 0.0047 (334 hom.)
• Consequence: LHX4 NM_033343.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.338
• Publications: 6 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 1-180230592-T-C is Benign according to our data. Variant chr1-180230592-T-C is described in ClinVar as Benign. ClinVar VariationId is 293858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.338 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.128 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.63T>C	p.Gly21Gly	synonymous	Exon 1 of 6	NP_203129.1	A0A0S2Z5S4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHX4	ENST00000263726.4	TSL:1 MANE Select	c.63T>C	p.Gly21Gly	synonymous	Exon 1 of 6	ENSP00000263726.2	Q969G2
	LHX4	ENST00000930099.1		c.61+2T>C		splice_donor intron	N/A	ENSP00000600158.1
	LHX4	ENST00000558139.1	TSL:3	n.295T>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00604 AC: 919 AN: 152110 Hom.: 48 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.00374

Gnomad FIN AF: 0.00763

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.0121 AC: 3022 AN: 250626 AF XY: 0.0109

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.00489

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.132

Gnomad FIN exome AF: 0.00887

Gnomad NFE exome AF: 0.000751

Gnomad OTH exome AF: 0.00621

GnomAD4 exome AF: 0.00465 AC: 6800 AN: 1461358 Hom.: 334 Cov.: 30 AF XY: 0.00454 AC XY: 3302 AN XY: 727028

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00467 AC: 209 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.124 AC: 4919 AN: 39698

South Asian (SAS) AF: 0.00370 AC: 319 AN: 86242

European-Finnish (FIN) AF: 0.00879 AC: 468 AN: 53214

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.000324 AC: 360 AN: 1111734

Other (OTH) AF: 0.00861 AC: 520 AN: 60382

GnomAD4 genome AF: 0.00604 AC: 919 AN: 152226 Hom.: 48 Cov.: 31 AF XY: 0.00661 AC XY: 492 AN XY: 74418

African (AFR) AF: 0.000120 AC: 5 AN: 41540

American (AMR) AF: 0.00229 AC: 35 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.136 AC: 703 AN: 5154

South Asian (SAS) AF: 0.00374 AC: 18 AN: 4812

European-Finnish (FIN) AF: 0.00763 AC: 81 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000985 AC: 67 AN: 68016

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00389 Hom.: 29

Bravo AF: 0.00666

Asia WGS AF: 0.0410 AC: 144 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Short stature-pituitary and cerebellar defects-small sella turcica syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Benign	0.76
PhyloP100		0.34
PromoterAI		0.070	Neutral
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: rs75857235; hg19: chr1-180199727; COSMIC: COSV55378879;