chr21-44654475-C-A

Variant names:

• chr21-44654475-C-A
• rs782257584
• NM_198698.1:c.140G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198698.1(KRTAP12-4):​c.140G>T​(p.Arg47Leu) 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 benign outcome for this variant. 15/22 in silico tools predict a benign 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. R47Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KRTAP12-4 NM_198698.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.23
• Publications: 0 publications found

Genes affected

KRTAP12-4 (HGNC:20532): (keratin associated protein 12-4) Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

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

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

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049869597).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198698.1. 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
	KRTAP12-4	NM_198698.1	MANE Select	c.140G>T	p.Arg47Leu	missense	Exon 1 of 1	NP_941971.1	P60329
	TSPEAR	NM_144991.3	MANE Select	c.82+56958G>T		intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.-123+36070G>T		intron	N/A	NP_001258966.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP12-4	ENST00000391618.1	TSL:6 MANE Select	c.140G>T	p.Arg47Leu	missense	Exon 1 of 1	ENSP00000375476.1	P60329
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.82+56958G>T		intron	N/A	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000943283.1		c.82+56958G>T		intron	N/A	ENSP00000613342.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.027
DANN	Benign	0.69
DEOGEN2	Benign	0.027	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.00091	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.00052	T
MetaRNN	Benign	0.050	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		-2.2
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.035
Sift	Benign	0.15	T
Sift4G	Benign	0.28	T
Polyphen		0.0070	B
Vest4		0.13
MutPred		0.28		Gain of catalytic residue at R47 (P = 0.0784)
MVP		0.27
MPC		0.016
ClinPred		0.089	T
GERP RS		-8.1
PromoterAI		0.011	Neutral
Varity_R		0.040
gMVP		0.058
Mutation Taster		=100/0	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: rs782257584; hg19: chr21-46074392;