2-9986209-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_198182.3(GRHL1):​c.1196C>T​(p.Thr399Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

GRHL1
NM_198182.3 missense

Scores

14
4
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91
Variant links:
Genes affected
GRHL1 (HGNC:17923): (grainyhead like transcription factor 1) This gene encodes a member of the grainyhead family of transcription factors. The encoded protein can exist as a homodimer or can form heterodimers with sister-of-mammalian grainyhead or brother-of-mammalian grainyhead. This protein functions as a transcription factor during development. [provided by RefSeq, Jun 2009]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GRHL1NM_198182.3 linkc.1196C>T p.Thr399Ile missense_variant 9/16 ENST00000324907.14 NP_937825.2 Q9NZI5-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GRHL1ENST00000324907.14 linkc.1196C>T p.Thr399Ile missense_variant 9/161 NM_198182.3 ENSP00000324693.9 Q9NZI5-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000370
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 20, 2023The c.1196C>T (p.T399I) alteration is located in exon 9 (coding exon 9) of the GRHL1 gene. This alteration results from a C to T substitution at nucleotide position 1196, causing the threonine (T) at amino acid position 399 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.18
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.85
D;.
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Uncertain
0.25
D
MetaRNN
Pathogenic
0.97
D;D
MetaSVM
Uncertain
-0.16
T
MutationAssessor
Pathogenic
3.9
H;.
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-5.4
D;.
REVEL
Pathogenic
0.86
Sift
Pathogenic
0.0
D;.
Sift4G
Uncertain
0.0030
D;D
Polyphen
1.0
D;D
Vest4
0.98
MutPred
0.89
Gain of sheet (P = 0.0827);.;
MVP
0.44
MPC
1.2
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.95
gMVP
0.87

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1668410264; hg19: chr2-10126337; API