12-120999579-A-T

Variant names:

• chr12-120999579-A-T
• rs1169305
• NM_000545.8:c.1720A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000545.8(HNF1A):​c.1720A>T​(p.Ser574Cys) 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. 12/20 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. S574D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.738
• Publications: 65 publications found

Genes affected

HNF1A (HGNC:11621): (HNF1 homeobox A) The protein encoded by this gene is a transcription factor required for the expression of several liver-specific genes. The encoded protein functions as a homodimer and binds to the inverted palindrome 5'-GTTAATNATTAAC-3'. Defects in this gene are a cause of maturity onset diabetes of the young type 3 (MODY3) and also can result in the appearance of hepatic adenomas. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]

HNF1A Gene-Disease associations (from GenCC):

• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• type 1 diabetes mellitus 20

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• maturity-onset diabetes of the young type 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hyperinsulinism due to HNF1A deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• nonpapillary renal cell carcinoma

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22391927).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.1720A>T	p.Ser574Cys	missense_variant	Exon 9 of 10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.1741A>T	p.Ser581Cys	missense_variant	Exon 9 of 10		NP_001293108.2
HNF1A	NM_001406915.1	c.1528A>T	p.Ser510Cys	missense_variant	Exon 8 of 9		NP_001393844.1
HNF1A	XM_024449168.2	c.1813A>T	p.Ser605Cys	missense_variant	Exon 8 of 9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.1720A>T	p.Ser574Cys	missense_variant	Exon 9 of 10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 56

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.0	.;D;.;T;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.25	T;T;T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.0	.;.;.;.;.
PhyloP100		0.74
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.3	N;.;.;N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.021	D;.;.;D;D
Sift4G	Benign	0.11	T;T;T;T;T
Vest4		0.25
ClinPred		0.39	T
GERP RS		2.6
gMVP		0.45
Mutation Taster		=98/2	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: rs1169305; hg19: chr12-121437382;