rs727503133

Variant names:

• chr6-35805884-G-A
• rs727503133
• NM_182548.4:c.214G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_182548.4(LHFPL5):​c.214G>A​(p.Val72Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LHFPL5 NM_182548.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.36
• Publications: 1 publications found

Genes affected

LHFPL5 (HGNC:21253): (LHFPL tetraspan subfamily member 5) This gene is a member of the lipoma HMGIC fusion partner (LHFP) gene family, which is a subset of the superfamily of tetraspan transmembrane protein encoding genes. Mutations in this gene result in deafness in humans, and a mutation in a similar gene in mice results in deafness and vestibular dysfunction with severe degeneration of the organ of Corti. It is proposed to function in hair bundle morphogenesis. [provided by RefSeq, Jul 2008]

LHFPL5 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 67

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a chain LHFPL tetraspan subfamily member 5 protein (size 218) in uniprot entity LHPL5_HUMAN there are 8 pathogenic changes around while only 3 benign (73%) in NM_182548.4
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182548.4. 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
	LHFPL5	NM_182548.4	MANE Select	c.214G>A	p.Val72Met	missense	Exon 1 of 4	NP_872354.1	Q8TAF8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LHFPL5	ENST00000360215.3	TSL:1 MANE Select	c.214G>A	p.Val72Met	missense	Exon 1 of 4	ENSP00000353346.1	Q8TAF8
	LHFPL5	ENST00000651132.1		c.214G>A	p.Val72Met	missense	Exon 4 of 7	ENSP00000498322.1	Q8TAF8
	LHFPL5	ENST00000651676.1		c.214G>A	p.Val72Met	missense	Exon 1 of 4	ENSP00000498699.1	Q8TAF8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	0.011
Eigen_PC	Benign	0.074
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.90	T
PhyloP100		7.4
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.28
Sift	Benign	0.032	D
Sift4G	Benign	0.14	T
Polyphen		0.90	P
Vest4		0.21
MutPred		0.48		Gain of sheet (P = 0.0221)
MVP		0.48
MPC		0.60
ClinPred		0.90	D
GERP RS		4.7
PromoterAI		-0.024	Neutral
Varity_R		0.38
Mutation Taster		=84/16	polymorphism

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: rs727503133; hg19: chr6-35773661; COSMIC: COSV104420433;