NM_144991.3:c.1224C>G

Variant names:

• chr21-44525765-G-C
• rs35028190
• NM_144991.3:c.1224C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144991.3(TSPEAR):​c.1224C>G​(p.His408Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0609 in 1,614,070 control chromosomes in the GnomAD database, including 3,432 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 0.047 (217 hom., cov: 33)
  • Exomes 𝑓: 0.062 (3215 hom.)
• Consequence: TSPEAR NM_144991.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.326
• Publications: 10 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-AS1 (HGNC:1271): (TSPEAR antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022302568).
• BP6: Variant 21-44525765-G-C is Benign according to our data. Variant chr21-44525765-G-C is described in ClinVar as Benign. ClinVar VariationId is 227130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.068 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPEAR	NM_144991.3	MANE Select	c.1224C>G	p.His408Gln	missense	Exon 8 of 12	NP_659428.2
	TSPEAR	NM_001272037.2		c.1020C>G	p.His340Gln	missense	Exon 9 of 13	NP_001258966.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.1224C>G	p.His408Gln	missense	Exon 8 of 12	ENSP00000321987.4
	TSPEAR	ENST00000397916.1	TSL:1	n.1179C>G		non_coding_transcript_exon	Exon 8 of 11
	TSPEAR	ENST00000642437.1		n.*1169C>G		non_coding_transcript_exon	Exon 9 of 13	ENSP00000496535.1

Frequencies

GnomAD3 genomes AF: 0.0472 AC: 7182 AN: 152106 Hom.: 217 Cov.: 33

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0331

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0193

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0697

Gnomad OTH AF: 0.0417

GnomAD2 exomes AF: 0.0479 AC: 12045 AN: 251484 AF XY: 0.0483

Gnomad AFR exome AF: 0.0105

Gnomad AMR exome AF: 0.0234

Gnomad ASJ exome AF: 0.0286

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.0666

Gnomad OTH exome AF: 0.0502

GnomAD4 exome AF: 0.0623 AC: 91140 AN: 1461846 Hom.: 3215 Cov.: 31 AF XY: 0.0613 AC XY: 44546 AN XY: 727224

African (AFR) AF: 0.00953 AC: 319 AN: 33480

American (AMR) AF: 0.0252 AC: 1126 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0293 AC: 767 AN: 26134

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39700

South Asian (SAS) AF: 0.0227 AC: 1954 AN: 86258

European-Finnish (FIN) AF: 0.102 AC: 5424 AN: 53408

Middle Eastern (MID) AF: 0.0265 AC: 153 AN: 5768

European-Non Finnish (NFE) AF: 0.0706 AC: 78472 AN: 1111986

Other (OTH) AF: 0.0483 AC: 2915 AN: 60390

GnomAD4 genome AF: 0.0472 AC: 7182 AN: 152224 Hom.: 217 Cov.: 33 AF XY: 0.0465 AC XY: 3461 AN XY: 74428

African (AFR) AF: 0.0122 AC: 508 AN: 41544

American (AMR) AF: 0.0331 AC: 506 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 108 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.0199 AC: 96 AN: 4820

European-Finnish (FIN) AF: 0.103 AC: 1094 AN: 10576

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0697 AC: 4739 AN: 68012

Other (OTH) AF: 0.0412 AC: 87 AN: 2110

Alfa AF: 0.0576 Hom.: 101

Bravo AF: 0.0398

TwinsUK AF: 0.0688 AC: 255

ALSPAC AF: 0.0758 AC: 292

ESP6500AA AF: 0.0134 AC: 59

ESP6500EA AF: 0.0647 AC: 556

ExAC AF: 0.0470 AC: 5703

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.0625

EpiControl AF: 0.0613

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 26, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

His408Gln in exon 8 of TSPEAR: This variant is not expected to have clinical sig nificance because it has been identified in 6.5% (556/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs35028190).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Benign	0.76
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.33
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.094
Sift	Benign	0.69	T
Sift4G	Benign	0.61	T
Polyphen		0.0030	B
Vest4		0.13
MutPred		0.27		Gain of catalytic residue at H408 (P = 0.0067)
MPC		0.052
ClinPred		0.000023	T
GERP RS		1.6
Varity_R		0.064
gMVP		0.19
Mutation Taster		=99/1	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: rs35028190; hg19: chr21-45945648; COSMIC: COSV107388292; COSMIC: COSV107388292;