rs1169305

Positions:

• chr12-120999579-A-C
• chr12-120999579-A-G
• chr12-120999579-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000545.8(HNF1A):​c.1720A>C​(p.Ser574Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S574G) has been classified as Benign.

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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18867612).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.1720A>C	p.Ser574Arg	missense_variant	9/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.1741A>C	p.Ser581Arg	missense_variant	9/10
HNF1A	NM_001406915.1	c.1528A>C	p.Ser510Arg	missense_variant	8/9
HNF1A	XM_024449168.2	c.1813A>C	p.Ser605Arg	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.1720A>C	p.Ser574Arg	missense_variant	9/10	1	NM_000545.8	P4

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	0.22
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	.;D;.;T;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.27	T;T;T;T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.19	T;T;T;T;T
MetaSVM	Benign	-0.52	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.1	N;.;.;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.048	D;.;.;D;T
Sift4G	Benign	0.46	T;T;T;T;T
Polyphen		0.018	.;.;.;.;B
Vest4		0.25
MutPred		0.44		.;.;.;.;Loss of glycosylation at S581 (P = 0.0238);
MVP		0.79
MPC		0.14
ClinPred		0.28	T
GERP RS		2.6
gMVP		0.43

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

Other links and lift over

dbSNP: rs1169305; hg19: chr12-121437382;