21-44499915-G-C

Variant names:

• chr21-44499915-G-C
• NM_144991.3:c.1878C>G
• TSPEAR p.Phe626Leu

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_144991.3(TSPEAR):​c.1878C>G​(p.Phe626Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F626S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSPEAR NM_144991.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.206
• Publications: 0 publications found

Genes affected

TSPEAR (HGNC:1268): (thrombospondin type laminin G domain and EAR repeats) This gene encodes a protein that contains a N-terminal thrombospondin-type laminin G domain and several tandem arranged epilepsy-associated repeats (EARs). A mutation in this gene is the cause of autosomal recessive deafness-98. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

TSPEAR Gene-Disease associations (from GenCC):

• ectodermal dysplasia 14, hair/tooth type with or without hypohidrosis

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive nonsyndromic hearing loss 98

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-44499916-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1197259.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.889

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144991.3. 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
	TSPEAR	NM_144991.3	MANE Select	c.1878C>G	p.Phe626Leu	missense	Exon 12 of 12	NP_659428.2
	TSPEAR	NM_001272037.2		c.1674C>G	p.Phe558Leu	missense	Exon 13 of 13	NP_001258966.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.1878C>G	p.Phe626Leu	missense	Exon 12 of 12	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000943283.1		c.2004C>G	p.Phe668Leu	missense	Exon 13 of 13	ENSP00000613342.1
	TSPEAR	ENST00000642437.1		n.*1823C>G		non_coding_transcript_exon	Exon 13 of 13	ENSP00000496535.1	A0A2R8YFK6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.058
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.21
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.028	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.29
gMVP		0.67
Mutation Taster		=59/41	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr21-45919798;