NM_198692.3:c.117G>A

Variant names:

• chr21-44646575-G-A
• rs201708271
• NM_198692.3:c.117G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_198692.3(KRTAP10-11):​c.117G>A​(p.Pro39Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,612,200 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (8 hom.)
• Consequence: KRTAP10-11 NM_198692.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.41
• Publications: 1 publications found

Genes affected

KRTAP10-11 (HGNC:20528): (keratin associated protein 10-11) 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 21-44646575-G-A is Benign according to our data. Variant chr21-44646575-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3777903.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-4.41 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198692.3. 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
	KRTAP10-11	NM_198692.3	MANE Select	c.117G>A	p.Pro39Pro	synonymous	Exon 1 of 1	NP_941965.2	P60412
	TSPEAR	NM_144991.3	MANE Select	c.82+64858C>T		intron	N/A	NP_659428.2
	TSPEAR	NM_001272037.2		c.-123+43970C>T		intron	N/A	NP_001258966.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP10-11	ENST00000334670.9	TSL:6 MANE Select	c.117G>A	p.Pro39Pro	synonymous	Exon 1 of 1	ENSP00000334197.8	P60412
	TSPEAR	ENST00000323084.9	TSL:1 MANE Select	c.82+64858C>T		intron	N/A	ENSP00000321987.4	Q8WU66-1
	TSPEAR	ENST00000943283.1		c.82+64858C>T		intron	N/A	ENSP00000613342.1

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 336 AN: 152010 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00319

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00231 AC: 574 AN: 248064 AF XY: 0.00229

Gnomad AFR exome AF: 0.000528

Gnomad AMR exome AF: 0.000812

Gnomad ASJ exome AF: 0.0165

Gnomad EAS exome AF: 0.000831

Gnomad FIN exome AF: 0.00130

Gnomad NFE exome AF: 0.00280

Gnomad OTH exome AF: 0.00183

GnomAD4 exome AF: 0.00270 AC: 3942 AN: 1460072 Hom.: 8 Cov.: 151 AF XY: 0.00264 AC XY: 1916 AN XY: 726368

African (AFR) AF: 0.000598 AC: 20 AN: 33420

American (AMR) AF: 0.000828 AC: 37 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0157 AC: 410 AN: 26102

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39694

South Asian (SAS) AF: 0.000163 AC: 14 AN: 86144

European-Finnish (FIN) AF: 0.000956 AC: 51 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4538

European-Non Finnish (NFE) AF: 0.00292 AC: 3245 AN: 1111864

Other (OTH) AF: 0.00259 AC: 156 AN: 60262

GnomAD4 genome AF: 0.00221 AC: 336 AN: 152128 Hom.: 2 Cov.: 33 AF XY: 0.00215 AC XY: 160 AN XY: 74388

African (AFR) AF: 0.000578 AC: 24 AN: 41508

American (AMR) AF: 0.000850 AC: 13 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3466

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10594

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00319 AC: 217 AN: 67968

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00406 Hom.: 2

Bravo AF: 0.00227

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00356

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.56
DANN	Benign	0.64
PhyloP100		-4.4
PromoterAI		0.0026	Neutral
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: rs201708271; hg19: chr21-46066492; COSMIC: COSV58178805;